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Conformationally Defined Analogs of Methamphetamine GARY L. GRUNEWALD, MARY WEIR CREESE, and D. ERIC WALTERS Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045 A major objective of our research program is to elucidate the molecular events involved i n the i n t e r action of sympathomimetic amines with the adrenergic neuroeffector complex. A major portion of t h i s work i s aimed at the delineation of the conformational r e q u i r e ments for optimal i n t e r a c t i o n of sympathomimetic amines with t h e i r various p h y s i o l o g i c a l l y s i g n i f i c a n t i n t e r active s i t e s within the synaptic area (pre- and post-synaptic receptors, presynaptic uptake and storage s i t e s and metabolic enzymes). Such knowledge would be p r e r e q u i s i t e for r a t i o n a l design of s p e c i f i c chemical agents to s e l e c t i v e l y modify neurotransmitter-receptor interactions and to eventually replace drugs of less specificity. Any discussion of s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s among sympathomimetic amines must be undertaken i n terms of the m u l t i p l i c i t y of p h y s i o l o g i c a l l y important s i t e s within the noradrenergic synapse with which such amines can p o t e n t i a l l y i n t e r a c t . A generalized synapse of t h i s type i s depicted i n Figure 1, and consists of the following generally accepted points of molecular physiology. Consider first the presynaptic events. Depolarization of the nerve ending r e s u l t s i n elevated i n t r a neuronal Ca l e v e l s and concomitant exocytotic release of norepinephrine from the storage granule (1,2,3) where norepinephrine i s stored i n high concentrations as an osmotically i n e r t complex with ATP (4,5). ++

A l t h o u g h most n e u r o n a l n o r e p i n e p h r i n e e x i s t s i n t h i s v e s i c u l a r pool, there i s also a small e x t r a v e s i c u l a r p o o l which has been i n t e r p r e t e d i n terms o f n o r e p i n e p h r i n e i o n i c a l l y bound t o s o l u b l e c y t o p l a s m i c c o n s t i t u e n t s ((5) . The c y t o p l a s m i c p o o l o f n o r e p i n e p h r i n e i n f a c t i s m a i n t a i n e d a t i t s low l e v e l by v e s i c u l a r s t o r a g e o f n o r e p i n e p h r i n e and by o x i d a t i v e d e a m i n a t i o n 0-8412-0521-3/79/47-112-439$ 12.25/0 © 1979 A m e r i c a n C h e m i c a l Society

Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

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Figure 1.

The noradrenergic nerve ending


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of n o r e p i n e p h r i n e v i a m i t o c h o n d r i a l monoamine o x i d a s e (MAO). Thus, i n h i b i t i o n o f MAO (pargyline) provides a means o f s w e l l i n g the e x t r a v e s i c u l a r n o r e p i n e p h r i n e compartment (7). The v e s i c u l a r p o o l can be o b l a t e d a l t o g e t h e r by t r e a t m e n t w i t h r e s e r p i n e which i r r e v e r s i b l y i n h i b i t s the v e s i c u l a r uptake o f n o r e p i n e p h r i n e (*L'D · While d e p o l a r i z a t i o n r e l e a s e s o n l y v e s i c u l a r n o r e p i n e p h r i n e i n a C a - d e p e n d e n t manner (10), i n d i r e c t l y a c t i n g sympathomimetic agents w i l l d i s p l a c e n o r e p i n e p h r i n e from both s t o r a g e forms i n a Ca independent manner (11,12). Norepinephrine r e l e a s e d i n t o the s y n a p t i c area i s r e n d e r e d i n a c t i v e e i t h e r by O - m e t h y l a t i o n (primarily meta but some para) v i a c a t e c h o l O - m e t h y l t r a n s f e r a s e (13) o r by uptake by the n e u r o n a l amine uptake system. U t i l i z i n g the i n w a r d l y - d i r e c t e d N a c o n c e n t r a t i o n g r a d i e n t m a i n t a i n e d by the n e u r o n a l membrane ( N a + K ) ATPase, n o r e p i n e p h r i n e i s c o - t r a n s p o r t e d w i t h N a in a f a c i l i t a t e d d i f f u s i o n p r o c e s s which appears t o be c a r r i e r - m e d i a t e d (14 ,l!p) . I n h i b i t o r s o f (Na + Κ )-ATPase w i l l a n t a g o n i z e n o r e p i n e p h r i n e a c c u m u l a t i o n as w i l l sympathomimetic amines which c o m p e t i t i v e l y b i n d t o the uptake c a r r i e r (15). C o c a i n e and d e s i p r a m i n e (DMI) b o t h d i s p l a y a h i g h a f f i n i t y f o r the c a r r i e r system, thus i n h i b i t i n g the uptake o f n o r e p i n e p h r i n e . P o s t s y n a p t i c a l l y n o r e p i n e p h r i n e may i n t e r a c t w i t h a- o r β-receptors, which c o u p l e w i t h an a d e n y l a t e (or guanylate) c y c l a s e t o i n i t i a t e p o s t s y n a p t i c events (16,17). P r e s y n a p t i c a- and β-receptors have a l s o been i m p l i c a t e d i n the m o d u l a t i o n o f t r a n s m i t t e r r e l e a s e . While an a d e n y l a t e c y c l a s e has been a s s o c i a t e d w i t h the p r e s y n a p t i c β-receptor, the p r e s y n a p t i c α-receptor appears t o be i n v o l v e d o n l y w i t h m o d u l a t i o n o f C a f l u x e s (18,19). S t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s (SAR) i n sympa thomimetic amines must then d e a l w i t h t h e e f f e c t o f m o l e c u l a r s t r u c t u r e on: 1) The i n h i b i t i o n o f n e u r o n a l t r a n s m i t t e r uptake. 2) The uptake and r e t e n t i o n o f the agents them selves . 3) The r e l e a s e o f t r a n s m i t t e r from i t s s t o r a g e sites. 4) D i r e c t r e c e p t o r a c t i v i t y o f the amines. 5) C o m p e t i t i v e b i n d i n g t o the a c t i v e s i t e s o f m e t a b o l i c enzymes. Unless these e f f e c t s are c a r e f u l l y s o r t e d out, e f f o r t s to d e s i g n s e l e c t i v e agents a r e thwarted from the outset. A r e v i e w o f SAR w i t h i n each d i v i s i o n o f a c t i o n would be i m p o s s i b l e w i t h i n the c o n f i n e s o f the p r e s e n t ++

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discussion. The r e a d e r i s r e f e r r e d elsewhere f o r t h e g e n e r a l c o n c l u s i o n s o f SAR on t h e c o m p e t i t i v e i n h i b i t i o n o f t h e n e u r o n a l uptake o f n o r e p i n e p h r i n e (20,21, 221,23) , t r a n s p o r t o f n o r e p i n e p h r i n e by t h e c a r r i e r (24TT r e l e a s e o f p r e v i o u s l y accumulated n o r e p i n e p h r i n e (25), i n t e r a c t i o n o f d i r e c t l y - a c t i n g sympathomimetic a g o n i s t s on t h e a - and 3 - r e c e p t o r s (26) and t h e subs t r a t e s p e c i f i c i t y f o r catechol O-methyltransferase (2J_,20). These c o n c l u s i o n s o f SAR i l l u s t r a t e t h a t s e l e c t i v i t y o f p h a r m a c o l o g i c a l a c t i o n i s n o t always p o s s i b l e through gross s t r u c t u r a l manipulation alone. S e v e r a l i n t e r a c t i v e s i t e s can d i s p l a y s i m i l a r s t r u c t u r a l preference. D e s p i t e t h e d e t a i l o f t h e s e SAR s t u d i e s , t h e e x a c t n a t u r e o f t h e n e u r o t r a n s m i t t e r (or d r u g ) r e c e p t o r complex remains unknown. The p o s s i b i l i t y t h a t d i f f e r e n t s i t e s o f drug a c t i o n r e q u i r e d i f f e r e n t c o n f o r m a t i o n a l arrangements o f t h e a g o n i s t , t h e r e b y u n c o v e r i n g a new dimension o f drug s e l e c t i v i t y n o t p o s s i b l e through g r o s s s t r u c t u r a l m a n i p u l a t i o n a l o n e , w i l l be d i s c u s s e d below. Techniques f o r A s s e s s i n g C o n f o r m a t i o n - A c t i v i t y Relationships Conformation-activity r e l a t i o n s h i p s are c o n s i d e r a b l y more d i f f i c u l t t o d e l i n e a t e than a r e structure-activity relationships. In the l a t t e r case, one needs o n l y t o modify t h e s t r u c t u r e o f an a c t i v e s u b s t a n c e and t o d e t e r m i n e t h e p h a r m a c o l o g i c a l e f f e c t s i n d u c e d by t h e s t r u c t u r a l change. Most a c t i v e a d r e n e r g i c a g e n t s , however, a r e c o n f o r m a t i o n a l l y m o b i l e ; r o t a t i o n about s i n g l e bonds i s u s u a l l y f a c i l e and r a p i d . F o r t h i s r e a s o n , most a d r e n e r g i c agents provide very l i t t l e d i r e c t information regarding conformational e f f e c t s . A number o f t e c h n i q u e s have been a p p l i e d t o t h e study o f c o n f o r m a t i o n - a c t i v i t y r e l a t i o n s h i p s : x-ray c r y s t a l structure determination, molecular o r b i t a l c a l c u l a t i o n s o f low-energy c o n f o r m a t i o n s , n u c l e a r magnetic resonance d e t e r m i n a t i o n s o f s o l u t i o n c o n f o r m a t i o n s , and t h e p r e p a r a t i o n o f c o n f o r m a t i o n a l l y r e s t r i c t e d analogs. The f i r s t t h r e e methods a r e d i r e c t e d toward d e t e r m i n i n g which c o n f o r m a t i o n (or which c o n f o r m a t i o n s ) i s (are) most f a v o r a b l e ; t h e assumption i s made t h a t an e n e r g e t i c a l l y p r e f e r r e d c o n f o r m a t i o n w i l l be t h e b i o l o g i c a l l y a c t i v e c o n f o r mation. T h i s need n o t be t h e c a s e ; P o r t o g h e s e ' s s u g g e s t i o n (29) r e g a r d i n g a " h i g h - e n e r g y " c o n f o r m a t i o n would n o t be c o n s i s t e n t w i t h such an assumption. Nevertheless, the p o s s i b i l i t y that a favorable


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c o n f o r m a t i o n might c o r r e s p o n d t o an a c t i v e one has s e r v e d as a s t a r t i n g p o i n t f o r a l a r g e amount o f research. The use o f c o n f o r m a t i o n a l l y - r e s t r i c t e d a n a l o g s p r e c l u d e s t h e n e c e s s i t y o f such an assumption, but t h i s method a l s o has i t s l i m i t a t i o n s . We w i s h t o combine a number o f t h e s e t e c h n i q u e s i n a s i n g l e l a b o r a t o r y w i t h t h e hope t h a t t h e advantages o f each approach w i l l be m a g n i f i e d and t h e d i s a d v a n t a g e s minimized. X-Ray C r y s t a l l o g r a p h y . T h i s approach i s based on the assumption t h a t a low-energy c o n f o r m a t i o n s h o u l d be the c o n f o r m a t i o n r e c o g n i z e d by t h e r e c e p t o r . (Receptor i s here used l o o s e l y t o r e f e r t o any s i t e o f i n t e r a c t i o n w i t h t h e a g o n i s t o r a n t a g o n i s t m o l e c u l e ) . The c r y s t a l l i n e form o f a s u b s t a n c e s h o u l d c e r t a i n l y be a r e l a t i v e l y low-energy and s t a b l e c o n f o r m a t i o n . I n a d d i t i o n , s t r u c t u r a l and c o n f o r m a t i o n a l f e a t u r e s a r e d e l i n e a t e d w i t h a h i g h degree o f a c c u r a c y by x - r a y diffraction. S e v e r a l n e g a t i v e f a c t o r s s h o u l d be p o i n t e d o u t , however. F i r s t , t h e m o l e c u l e i n t h e s o l i d s t a t e has a much d i f f e r e n t environment from t h a t in dilute solution. A l s o , i f a s u b s t a n c e has two o r more r e l a t i v e l y s t a b l e c o n f o r m a t i o n s , o n l y one o f t h e s e i s l i k e l y t o e x i s t i n the c r y s t a l , while the other(s) would go u n d e t e c t e d . F i n a l l y , c r y s t a l packing forces may cause d i s t o r t i o n s o f t h e m o l e c u l e whenever t h e i n c r e a s e d s t r a i n energy i s compensated f o r by enhanced intermolecular interactions. A t l e a s t e i g h t e e n p h e n y l e t h y l a m i n e s have been examined by x - r a y c r y s t a l l o g r a p h y . Among t h e s e a r e p h e n y l e t h y l a m i n e h y d r o c h l o r i d e (30) , e p h e d r i n e h y d r o c h l o r i d e (31), e p h e d r i n e monohydrogen phosphate monohydrate (32) , e p h e d r i n e d i h y d r o g e n phosphate (33) , dopamine h y d r o c h l o r i d e (34) , 5-hydroxydopamine h y d r o c h l o r i d e (35,) , 6-hydroxydopamine h y d r o c h l o r i d e (36.) / e p i n e p h r i n e hydrogen t a r t r a t e (37) , n o r e p i n e p h r i n e h y d r o c h l o r i d e (38), i s o p r o t e r e n o l s u l f a t e (39) , 2,4,5trimethoxyamphetamine h y d r o c h l o r i d e (40), 4 - e t h y l - 2 , 5 dimethoxyamphetamine (41) , m e s c a l i n e hydrobromide ( 4 2 ) , and m e s c a l i n e h y d r o c h l o r i d e ( 4 3 ) . U s i n g t h e c o n v e n t i o n s shown i n F i g u r e 2, s e v e r a l o b s e r v a t i o n s may be made r e g a r d i n g t h e s o l i d s t a t e conformations o f these phenylethylamines. First, f i f t e e n o f t h e e i g h t e e n compounds have t h e n i t r o g e n atom and t h e a r o m a t i c r i n g i n an extended c o n f o r m a t i o n (ΤΛ = 180°). I t i s i n t e r e s t i n g t o note t h a t m e s c a l i n e h y d r o c h l o r i d e e x i s t s i n an extended c o n f o r m a t i o n , w h i l e t h e hydrobromide has a gauche c o n f o r m a t i o n . S i n c e t h e i o n i c r a d i i o f t h e a n i o n s (44) a r e v e r y



444

Figure 2. 2-Phenylethyhmine (unless otherwise stated, the numbering system shown is used throughout most of this paper in describing phenylethylamines)

6'

t

2 t

2

N u m b e r of observations 3η

2H

0

30

Figure 3.

60

90

120

150

Distribution of values of TJ (see text)


180

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n e a r l y e q u a l ( C l = 1 . 8 0 A; Br = 1 . 9 5 A ) , i t would appear t h a t b o t h c o n f o r m a t i o n s a r e r e a s o n a b l y s t a b l e and might e x i s t i n d i l u t e s o l u t i o n . Among t h e t h r e e compounds e x i s t i n g i n a gauche c o n f o r m a t i o n ( τ ^ = 6 0 ° ) , m e s c a l i n e hydrobromide and 2 , 4 , 5 - t r i methoxyamphetamine h y d r o c h l o r i d e a r e p o t e n t h a l l u cinogens , while 4-ethyl-2,5-dimethoxyamphetamine i s r e p o r t e d t o cause e u p h o r i a and a f e e l i n g o f enhanced self-awareness ( 4 5 ) . In F i g u r e 3 , t h e T]_ v a l u e s a r e r e p r e s e n t e d graphically. I t may be seen t h a t most o f t h e s e v a l u e s f a l l i n t h e range o f 6 7 ° t o 9 7 ° , i n d i c a t i n g t h a t t h e s i d e c h a i n i s u s u a l l y d i r e c t e d away from the p l a n e o f t h e a r o m a t i c r i n g . The two e x c e p t i o n s a r e 5-hydroxydopamine ( 5 9 ° ) and e p i n e p h r i n e hydrogen tartrate ( 1 7 9 ° ) . In the l a t t e r case, the authors ( 3 7 ) suggest t h a t t h e e x t r e m e l y dense p a c k i n g o f the s t r u c t u r e and t h e numerous hydrogen bonds may cause t h e m o l e c u l e t o assume t h i s u n u s u a l c o n f o r m a t i o n . Molecular O r b i t a l Calculations. Theoretical c a l c u l a t i o n s o f m o l e c u l a r p r o p e r t i e s have become r e a s o n a b l y a c c u r a t e and r e l a t i v e l y easy t o c a r r y o u t i n r e c e n t y e a r s . Atomic c o o r d i n a t e s from x - r a y s t r u c t u r e d e t e r m i n a t i o n s o r s t a n d a r d bond l e n g t h s and a n g l e s can s e r v e as t h e i n p u t , and a wide range o f p r o p e r t i e s may be d e t e r m i n e d . Of p a r t i c u l a r i n t e r e s t t o us i s t h e d e t e r m i n a t i o n o f t h e r e l a t i v e e n e r g i e s of v a r i o u s conformations o f a molecule, or the r e l a t i v e p o p u l a t i o n s o f a s e r i e s o f conformers. Rotational b a r r i e r s , which can a f f e c t i n t e r c o n v e r s i o n among c o n f o r m e r s , can a l s o be e s t i m a t e d . The assumption i s a g a i n made t h a t a c o n f o r m a t i o n which predominates i n s o l u t i o n s h o u l d be b i o l o g i c a l l y a c t i v e . Other parameters (such as charge d i s t r i b u t i o n ) which r e f l e c t the c a p a c i t y f o r e l e c t r o s t a t i c i n t e r a c t i o n s a t v a r i o u s p o i n t s on t h e m o l e c u l e can be c a l c u l a t e d . F i v e c o m p u t a t i o n a l methods have been a p p l i e d t o conformational studies of phenylethylamines. These a r e Extended Hiickel Theory (EHT) ( £ 6 ) , Complete N e g l e c t o f D i f f e r e n t i a l O v e r l a p (CNDO) ( 4 7 ) , I n t e r m e d i a t e N e g l e c t o f D i f f e r e n t i a l O v e r l a p (INDOl ( £ 8 ) , P e r t u r b a t i v e Configuration Interactions using Localized Orbitals (PCILO) ( £ 9 ) , and some ab i n i t i o (ΑΙ) ( 5 Ό ) p r o c e d u r e s . EHT i s r e l a t i v e l y easy and i n e x p e n s i v e t o u s e , b u t i t tends t o d i s t o r t e l e c t r o n d i s t r i b u t i o n i n systems c o n t a i n i n g heteroatoms. I n EHT, e l e c t r o n - r e p u l s i o n terms a r e n e g l e c t e d , c a u s i n g a tendency t o p r e d i c t u n r e a l i s t i c a l l y low e n e r g i e s f o r gauche and e c l i p s e d conformations. CNDO and INDO t a k e i n t o account some


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446

DRUG DESIGN

i m p o r t a n t e l e c t r o n - r e p u l s i o n terms, b u t gauche and e c l i p s e d c o n f o r m a t i o n s a r e a g a i n p r e d i c t e d t o be t o o stable r e l a t i v e t o staggered conformations. CNDO and INDO a r e r e f e r r e d t o as " s e m i - e m p i r i c a l " because t h e y can be " p a r a m e t e r i z e d " ; c e r t a i n v a r i a b l e s i n t h e computation a r e a s s i g n e d v a l u e s which w i l l g i v e good r e s u l t s f o r a g i v e n c l a s s o f compounds o r f o r a g i v e n c h e m i c a l p r o p e r t y . A l l o f t h e above methods e x c e p t PCILO employ t h e H a r t r e e - F o c k a p p r o x i m a t i o n i n t h e i r c a l c u l a t i o n s ; t h i s approximation i s v a l i d only a t o r near low-energy s t a t e s o f t h e m o l e c u l e . For this reason, r o t a t i o n a l b a r r i e r s are often overestimated. PCILO, on t h e o t h e r hand, p r e d i c t s s l i g h t l y l o w e r - t h a n normal r o t a t i o n a l b a r r i e r s . AI methods use much more s o p h i s t i c a t e d c o m p u t a t i o n s , b u t t h e b a s i s s e t s from which m o l e c u l e s a r e c o n s t r u c t e d a r e o f t e n e i t h e r t o o s m a l l t o g i v e good r e s u l t s o r t o o e x p e n s i v e t o use f o r m o l e c u l e s o f more t h a n a few atoms. A more mathe m a t i c a l comparison o f methods has been p r e s e n t e d by Hoyland (51.) . T a b l e I l i s t s t h e compounds which have been s t u d i e d by m o l e c u l a r o r b i t a l methods. T h i s l i s t i n c l u d e s d i r e c t l y and i n d i r e c t l y a c t i n g a g o n i s t s as w e l l as a n t a g o n i s t s . A l t h o u g h t h e e n e r g i e s d e t e r m i n e d by t h e s e methods a r e n o t f r e e e n e r g i e s s i n c e e n t r o p i e e f f e c t s a r e n o t t a k e n i n t o c o n s i d e r a t i o n , energy d i f f e r e n c e s among c l o s e l y r e l a t e d compounds appear t o be q u i t e a c c u r a t e l y d e t e r m i n e d . Conformational r e s u l t s are often s e n s i t i v e t o the i n p u t geometry used. F o r i n s t a n c e , Pullman at at. (68) c a r r i e d o u t two PCILO c a l c u l a t i o n s f o r m e s c a l i n e , u s i n g the x-ray c r y s t a l geometries obtained f o r t h e hydrobromide and h y d r o c h l o r i d e s a l t s ; t h e s e s a l t s e x i s t i n gauche and extended c o n f o r m a t i o n s , r e s p e c t i v e l y . In b o t h c a s e s t h e c a l c u l a t i o n s showed r e l a t i v e minima f o r b o t h c o n f o r m a t i o n s , and t h e s e minima d i f f e r e d by l e s s than one k c a l / m o l . I n each c a s e , however, t h e g l o b a l ( o v e r a l l ) minimum c o r r e s p o n d e d t o t h e c r y s t a l geometry. M a r t i n zt at. (70) have p u b l i s h e d a d e t a i l e d s t u d y o f p h e n y l e t h y l a m i n e , u t i l i z i n g EHT, CNDO, INDO, PCILO and A I . These a u t h o r s used s e m i - e m p i r i c a l methods t o g e n e r a t e a s e r i e s o f c o n f o r m a t i o n a l energy s u r f a c e s and then used an AI p r o c e d u r e w i t h a l a r g e b a s i s s e t f o r a few s e l e c t e d p o i n t s . EHT, CNDO and INDO a l l i n d i c a t e d a minimum f o r T± a t 9 0 ° ; EHT p r e d i c t s a r o t a t i o n a l b a r r i e r o f 7 k c a l / m o l , w h i l e CNDO and INDO show a b a r r i e r o f about 2 k c a l / m o l . PCILO g i v e s a r o t a t i o n a l b a r r i e r o f about 2 k c a l / m o l , b u t i t shows a v e r y broad minimum f o r τ ι , r a n g i n g from 4 5 ° t o 1 3 5 ° . With r e s p e c t t o r o t a t i o n about τ , t h e s e a u t h o r s found t h e extended 9


21.

GRUNEWALD E T A L .

Analogs

of

Methamphetamine

447

form t o be about 1 k c a l / m o l more s t a b l e than t h e gauche u s i n g EHT and Α Ι , w h i l e t h e gauche form appeard t o be about 1 k c a l / m o l more s t a b l e u s i n g CNDO, INDO and PCILO. The most e x t e n s i v e s t u d i e s o f p h e n y l e t h y l a m i n e s have been done by Pullman and coworkers (5>9,6J5,6T7,68) . T h e i r PCILO c a l c u l a t i o n s i n d i c a t e d t h a t gauche and t r a n s conformers have n e a r l y i d e n t i c a l e n e r g i e s i n t h e m a j o r i t y o f p h e n y l e t h y l a m i n e s and p h e n y l e t h a n o l a m i n e s studied. AI s t u d i e d were c a r r i e d o u t u s i n g t h r e e d i f f e r e n t b a s i s s e t s (67); t h e s e a l l i n d i c a t e d a s l i g h t b u t d e f i n i t e p r e f e r e n c e f o r gauche c o n f o r m e r s . These a u t h o r s n o t e d t h e preponderance o f extended conformers i n c r y s t a l s t r u c t u r e s and i n s o l u t i o n ; t h e y a t t r i b u t e d t h i s t o environmental f o r c e s . To t e s t t h i s h y p o t h e s i s , computations were r e p e a t e d w i t h t h e i n c l u s i o n o f water m o l e c u l e s , and a tendency toward the extended c o n f o r m a t i o n was i n d e e d o b s e r v e d . Thus, most o f t h e e v i d e n c e a v a i l a b l e from molecular o r b i t a l c a l c u l a t i o n s suggests t h a t both the extended and gauche c o n f o r m a t i o n s a r e r e a s o n a b l y s t a b l e . I t would appear unwise t o deduce t h a t one o f t h e s e c o n f o r m a t i o n s c a n be r e c o g n i z e d i n v i v o and t h e o t h e r n o t , s o l e l y on t h e b a s i s o f such c o m p u t a t i o n s . N u c l e a r M a g n e t i c Resonance. Through a c a r e f u l a n a l y s i s o f c o u p l i n g c o n s t a n t s , i t has sometimes been p o s s i b l e t o d e r i v e c o n f o r m a t i o n a l i n f o r m a t i o n from n u c l e a r magnetic resonance (NMR) s p e c t r a . This offers the advantage o f d i r e c t l y d e t e r m i n i n g s o l u t i o n c o n f o r m a t i o n s , which s h o u l d be more r e l e v a n t t o t h e b i o l o g i c a l s i t u a t i o n than would be s o l i d s t a t e o r i n vacuo c o n f o r m a t i o n s . Once a g a i n , t h e u n d e r l y i n g assumption i s t h a t a h i g h l y p o p u l a t e d conformer i s the a c t i v e s p e c i e s . T a b l e I I summarizes t h e c o n f o r m a t i o n a l s t u d i e s o f p h e n y l e t h y l a m i n e s which have been c a r r i e d o u t u s i n g NMR. In d e s c r i b i n g conformations, we w i l l use t h e f o l l o w i n g c o n v e n t i o n s (see F i g u r e 4 ) : 1) 1^ w i l l d e s i g n a t e t h a t c o n f o r m a t i o n i n which the n i t r o g e n atom i s a n t i p e r i p l a n a r w i t h respect t o the aromatic r i n g . 2) II_ w i l l d e s i g n a t e t h a t c o n f o r m a t i o n i n which the a r o m a t i c r i n g and t h e n i t r o g e n atom a r e i n a gauche r e l a t i o n s h i p ; i n compounds b e a r i n g a h y d r o x y l group on C-2, 11^ w i l l a l s o have t h e n i t r o g e n and oxygen atoms gauche t o each o t h e r , and i n amphetamines, I_I w i l l have t h e C - l methyl group a n t i p e r i p l a n a r w i t h r e s p e c t t o the a r o m a t i c r i n g . 3) I I I w i l l d e s i g n a t e a gauche r e l a t i o n s h i p

American Chemical Society Library 1155 f6th St. N. W. Olson and Christoffersen; Computer-Assisted Drug Design Washington, D. C. Society: 20036 ACS Symposium Series; American Chemical Washington, DC, 1979.


448

T a b l e I . Summary o f m o l e c u l a r o r b i t a l

studies of

phenylethylamines. Compound(s)

Method

Ref.

1.

Ephedrine Pseudoephedrine

EHT

52

2.

Norepinephrine

EHT

53

3. Dopamine

EHT

54

4. Dopamine

EHT

55

Norepinephrine Epinephrine N-Ethylnorepinephrine Isoproterenol

EHT, CNDO

56

Norepinephrine Norepinephrine·Li-H20

INDO

57

7. Dopamine

EHT

58

8.

PCILO

59

PCILO

60

10. P r a c t o l o l 1-(4 -methylphenyl)-2-isopropylaminoethanol 1-(4'-methylphenyl)-2-isopropylaminopropanol

CNDO

61

11.

Dopamine

EHT

62

12.

Norepinephrine Dopamine ( i n c l u d i n g meta- and para-anions)

CNDO

63

Phenylethylamine Norepinephrine Ephedrine Dopamine Tyramine Norephedrine Epinephrine Amphetamine

9. P h e n o x y e t h y l a m i n e

1


21.

GRUNEWALD E T A L .

Analogs of

Methamphetamine

449

T a b l e I (cont'd.) 13.

2,5-Dihydroxyphenylethylamine 2.3.4- T r i h y d r o x y p h e n y l e t h y l a m i n e 3.4.5- T r i h y d r o x y p h e n y l e t h y l a m i n e 2.3.6- T r i h y d r o x y p h e n y l e t h y l a m i n e 2,4,6-Trihydroxyphenylethylamine

CNDO

64

14.

2,4,5-Trimethoxyamphetamine 2,4,6-Trimethoxyamphetamine

PCILO

65

15.

Norepinephrine

CNDO

66

16.

Norepinephrine Amphetamine Epinephrine Isoproterenol Ephedrine

AI, PCILO

67

17. M e s c a l i n e 2.3.4- Trimethoxyamphetamine 2.4.5- Trimethoxyamphetamine 2.4.6- Trimethoxyamphetamine 2,4,5-Trihydroxyphenylethylamine 3,4,5-Trihydroxyphenylethylamine

PCILO

68

18.

CNDO

69

AI EHT CNDO INDO PCILO

70

Isoproterenol INPEA

19.

Phenylethylamine

2 0.

Phenylethylamine Amphetamine

AI

71

21.

Dopamine

INDO

72


COMPUTER-ASSISTED

450

DRUG

DESIGN

T a b l e I I . NMR c o n f o r m a t i o n a l s t u d i e s o f a d r e n e r g i c agents. Compound(s)

Solvent

Studied

Ref.

1. E p h e d r i n e Pseudoephedrine ( f r e e bases)

CDCI3

2. E p h e d r i n e Pseudoephedrine ( f r e e bases and HC1 s a l t s )

C C l ^ C ^ CDCl3,DMSO CF3COOH,D20

3. I s o p r o t e r e n o l Epinephrine (TMS e t h e r s )

CCI4

4. Dopamine HC1

D 0

5. Amphetamine ( f r e e base and HC1) Methamphetamine HC1 o-Methoxy-methamphetamine HC1 Benzphetamine HC1

D 0

6. F i v e dimethoxyamphetamines ( f r e e bases)

CDCI3

77

7. E i g h t e e n a r y l - s u b s t i t u t e d amphetamines ( f r e e bases) Nine a r y l - s u b s t i t u t e d amphetamines (HC1 s a l t s )

CDCI3

78

73

75

2

55

2

76

79

8. N - I s o p r o p y l - p - n i t r o p h e n y l e t h y l amine 9. Amphetamine

(free

base)

10. E l e v e n a d r e n e r g i c agents (HC1 s a l t s )

(HO)\^AH Ν Figure 4.

CDCI3

80

D 0

81

2

Ar

Ar

I

74

(HO)^P^H (CHJ

(HO}^P^H Η HI

Newman projections of the major conformations of phenylethylamines


21.

GRUNEWALD E T A L .

Analogs

of

Methamphetamine

451

between t h e a r o m a t i c r i n g and t h e n i t r o g e n atom; f u r t h e r , i n compounds b e a r i n g a hydroxy1 group on C-2, I I I w i l l have t h e oxygen atom a n t i p e r i p l a n a r with respect to the nitrogen atom, w h i l e f o r amphetamines, I I I w i l l i n d i c a t e t h a t t h e C - l methyl group i s a l s o gauche w i t h respect t o the aromatic r i n g . Hyne (73) i n v e s t i g a t e d t h e c o n f o r m a t i o n s o f e p h e d r i n e and pseudoephedrine as t h e f r e e bases i n d e u t e r i o c h l o r o f o r m (CDCI3). For ephedrine, the r a t i o o f c o n f o r m a t i o n s I_ ΓΙ and I I I was found t o be 40:40: 20, w h i l e f o r pseudoephedrine t h e r a t i o was 62:30:8. P o r t o g h e s e (74) s u b s e q u e n t l y r e i n v e s t i g a t e d t h e ephedrines. F o r e p h e d r i n e h y d r o c h l o r i d e i n D 0 , he found 90% o f t h e m a t e r i a l t o be i n c o n f o r m a t i o n s which p e r m i t t e d hydrogen bonding between t h e h y d r o x y l and amino groups (-i.e., 90% i n c o n f o r m a t i o n s ,1 and I I ) ; pseudoephedrine h y d r o c h l o r i d e was r e p o r t e d t o have 84% o f t h e extended c o n f o r m a t i o n !E and 16% gauche c o n f o r mers (ΓΙ and I I I ) . These r e s u l t s a r e a c c o u n t e d f o r by two f a c t o r s . F i r s t , hydrogen bonding i n t e r a c t i o n s f a v o r c o n f o r m a t i o n s I^ and I_I f o r b o t h e p h e d r i n e and pseudoephedrine. S e c o n d l y , t h e methyl s u b s t i t u e n t α t o t h e n i t r o g e n atom causes conformers 1^ and I I t o be s t e r i c a l l y l e s s f a v o r a b l e i n e p h e d r i n e , w h i l e T t makes I I and I I I l e s s f a v o r a b l e i n pseudoephedrine. A l a r g e number o f s u b s t i t u t e d amphetamines have been s t u d i e d by NMR. These r e s u l t s a r e summarized i n T a b l e I I I . I n a l l c a s e s , t h e extended c o n f o r m a t i o n (.1) predominated, making up 47-76% o f t h e conformer population. Conformer I_I, i n which t h e m e t h y l group on C - l i s d i r e c t e d away from t h e p h e n y l r i n g , i s a l s o p r e s e n t t o a s i g n i f i c a n t e x t e n t i n a l l c a s e s , making up 21-45% o f t h e sample. C o n f o r m a t i o n I I I , i n which the a r o m a t i c r i n g has gauche i n t e r a c t i o n s w i t h b o t h the m e t h y l group and t h e n i t r o g e n atom, makes up t h e r e m a i n i n g 0-12%. R e s u l t s f o r a v a r i e t y o f o t h e r a d r e n e r g i c agents have been c o m p i l e d i n T a b l e IV. As was t h e case f o r the amphetamines, t h e extended c o n f o r m a t i o n i s by f a r t h e predominant one, w i t h conformer ICI making a sub s t a n t i a l c o n t r i b u t i o n i n compounds b e a r i n g a h y d r o x y l group on C-2. The n o t a b l e e x c e p t i o n i s dopamine h y d r o c h l o r i d e , i n which 43% o f t h e extended c o n f o r m a t i o n and 57% o f t h e gauche c o n f o r m a t i o n were o b s e r v e d . In g e n e r a l , NMR experiments have been i n agreement with molecular o r b i t a l c a l c u l a t i o n s . Both extended and gauche conformers a r e u s u a l l y p r e s e n t t o a s i g n i f i c a n t e x t e n t , w i t h t h e extended conformer p r e d o m i n a t i n g . Again, the evidence a v a i l a b l e i s not s u f f i c i e n t t o f

2



/

/

2

2

2

2

3

3

3

3

3

3

2

3

2

2

3

3

HC1 HC1 HC1 HC1 HC1 HC1 HC1 fb

2

2,3-(OCH ) 2,4-(OCH ) 2,5-(OCH ) 3,4-(OCH ) 3,5-(OCH ) 2, 3,4-(OCH )3 3 4 5-(OCH )3

3

11. 12. 13. 14. 15. 16. 17. 18.

/

3

3

CH CH3 CH3, CH2C6H5 fb fb fb fb fb

3

fb HC1 HC1 HC1 HC1

Salt

2,3-(OCH )2 2,4-(OCH ) 2 5-(OCH3)2 3,4-(OCH ) 3,5-(OCH )

2-OCH

N-Alkyl

6. 7. 8. 9. 10.

1. 2. 3. 4. 5.

Aromatic Substitution a

CDCI3 CDCI3 CDCI3 CDCI3 CDCI3 CDCI3 CDCI3 CDCI3

CDCI3 CDCI3 CDCI3 CDCI3 CDCI3

2

2

D2O D2O D 0 D2O D 0

Solvent

68 66 65 76 75 65 72 72

67 62 64 64 65

50 50 55 47 64

32 34 35 23 25 35 28 28

21 26 24 25 23

39 45 39 36 35

78 78 78 78 78 78 78 80

77 77 77 77 77 12 12 12 11 12 0 0 0 1 0 0 0 0

76 76 76 76 76

Reference

11 5 6 17 1

Ratio of conformers^ I : II : III

T a b l e I I I . Amphetamine conformer d i s t r i b u t i o n s as d e t e r m i n e d by N.MR. (a) f b = f r e e base. (b) See F i g u r e 4 and t h e t e x t f o r c o n v e n t i o n s used i n s p e c i f y i n g conformations,


0

0

3 9 4 21

10 0 f

16

7 9 — 79 — 72

81 81 96

2

D 0 2

D 0 2

D 0 2

D 0 2

D2O D 0 2

D 0 2

D 0

HC1 HC1 HC1 HC1 HC1 HC1 HC1 HC1

8. P h e n y l e t h a n o l a m i n e

9. P h e n y l e p h r i n e

10. S y n e p h r i n e 11. N,N-Dimethyl-o-bromophenylethanolamine

12. N o r e p h e d r i n e

13. M e t a r a m i n o l

14. B u t a n e p h r i n e

15. P h e n y l e t h y l a m i n e

56

6

10 84

D 0

HC1

7. I s o p r o t e r e n o l

2

6

11 83

2

f

28 e

21

6

17

77

D 0

HC1

6. E p i n e p h r i n e

f

10

14

76

D2O

HC1

2

44

57

43

D 0

81

81

81

81

81

81

81

81

81

81

81

79

55 d

HC1

75 d

30

70

CCI4

fb

75

d

50

50

CCI4

fb

5. N o r e p i n e p h r i n e

4. N-Isopropyl-£-nitrophenylethylamine

3. Dopamine

2. E p i n e p h r i n e

1. I s o p r o t e r e n o l

b

T a b l e IV. NMR c o n f o r m a t i o n a l a n a l y s i s o f some p h e n y l e t h y l a m i n e s . (a) f b = f r e e base. (b) See F i g u r e 4 and t h e t e x t f o r c o n v e n t i o n s used i n s p e c i f y i n g c o n f o r m a t i o n . (c) Determined as t h e TMS e t h e r , (d) Sum o f conformers I I and I I I . (e) I I and I l l are e q u i v a l e n t ; sum o f I I and I I I . (f) Sum o f c o n f o r m e r s I_ and I I . Ratio of conformers Ref. I : II : III Compound Salta Solvent

i'

1

>»

•

6

Î

0 w

to


454 a s s e s s which c o n f o r m a t i o n

is biologically

active.

C o n f o r m a t i o n a l l y - R e s t r i c t e d Analogs. In p r e p a r i n g c o n f o r m a t i o n a l l y - r e s t r i c t e d analogs of a b i o l o g i c a l l y a c t i v e s u b s t a n c e , the e s s e n t i a l s t r u c t u r a l f e a t u r e s o f the a g o n i s t a r e b u i l t i n t o a m o l e c u l a r framework which has l i m i t e d c o n f o r m a t i o n a l m o b i l i t y . With t h i s approach i t i s no l o n g e r n e c e s s a r y t o assume t h a t a p r e d o m i n a t i n g c o n f o r m a t i o n i s a c t i v e , s i n c e the conf o r m a t i o n o f the message m o l e c u l e i s r e s t r i c t e d . When a c o n f o r m a t i o n a l l y - r e s t r i c t e d a n a l o g e x h i b i t s an a c t i v i t y , the c o n f o r m a t i o n a l possibilités r e s p o n s i b l e f o r t h a t a c t i v i t y are w e l l d e f i n e d . Unfortunately, the c o n v e r s e i s not t r u e — when such a n a l o g s a r e i n a c t i v e , t h e r e may be a number o f r e a s o n s o t h e r than i n c o r r e c t conformation. The e x t r a atoms n e c e s s a r y t o make the m o l e c u l e l e s s f l e x i b l e may s t e r i c a l l y i n t e r f e r e w i t h the d r u g - r e c e p t o r r e c o g n i t i o n p r o c e s s . In a d d i t i o n , the e x t r a atoms may a l t e r a b s o r p t i o n , t i s s u e d i s t r i b u t i o n , m e t a b o l i s m and o t h e r c e l l u l a r p r o c e s s e s . The i d e a l c o n f o r m a t i o n a l l y - r e s t r i c t e d a n a l o g s h o u l d p r o v i d e w e l l - d e f i n e d and u n d i s t o r t e d geometry w i t h as few e x t r a atoms as p o s s i b l e . Although a p l e t h o r a of r i g i d and s e m i - r i g i d a n a l o g s o f a d r e n e r g i c agents has appeared i n r e c e n t y e a r s , few have approached t h i s i d e a l ; most have shown l i t t l e o r no b i o l o g i c a l a c t i v i t y e x c e p t a t h i g h c o n c e n t r a t i o n s , and few show pronounced c o n f o r m a t i o n a l s e l e c t i v i t y . Comparisons a r e o f t e n d i f f i c u l t because t h e p h a r m a c o l o g i c a l t e s t i n g performed on t h e s e compounds ranges from s i m p l i s t i c to h i g h l y s o p h i s t i c a t e d . Some compounds would be e x p e c t e d t o show d i r e c t a c t i v i t y ( r e c e p t o r a c t i v a t i o n ) , some i n d i r e c t a c t i v i t y ( r e l e a s e o f n e u r o t r a n s m i t t e r ) , and some might have b o t h k i n d s o f a c t i v i t y . Table V i s a c o m p i l a t i o n o f t h e s e r i n g systems and t h e i r a p p l i cations. A d e t a i l e d r e v i e w i s beyond the scope o f t h i s d i s c u s s i o n , but some comments on the a n a l o g s o f amphetamine a r e p e r t i n e n t . Smissman and coworkers p r e p a r e d a l a r g e number o f t r a n s - d e c a l i n compounds (82-90). The t r a n s - d e c a l i n system i s r e a s o n a b l y r i g i d and may be e x p e c t e d t o p r o v i d e n e a r l y i d e a l d i h e d r a l a n g l e s ; however, the v e r y l a r g e number o f e x t r a atoms makes t h e s e compounds h i g h l y l i p o p h i l i c and c r e a t e s a g r e a t d e a l o f s t e r i c b u l k . The d e c a l i n amphetamine a n a l o g s ( s k e l e t o n 1 i n T a b l e V) were t e s t e d f o r t h e i r e f f e c t on motor a c t i v i t y (06), s i n c e amphetamine i t s e l f i s known t o i n c r e a s e motor activity. P a r a d o x i c a l l y , a l l f o u r compounds d e c r e a s e d motor a c t i v i t y . In a d d i t i o n , the extended conformer caused l a c h r y m a t i o n . L a t e r s t u d i e s (87,88,89) on


GRUNEWALD E T A L .

Analogs

of

Methamphetamine

455

T a b l e V. R i n g systems w h i c h have been u t l i z e d i n p r e p a r i n g c o n f o r m a t i o n a l l y - r e s t r i c t e d analogs of adrenergic agents.

S t r u c t u r a l Skeleton

Analogs

Number o f o f ; e x t r a atoms

Ref.

Ar , . Norephedrine ( On ; Anphetamine r*NHR Dopamine trans-decalin Norepinephrine

7-8

8290

Ph OH

Phenylethanol- 7 amine

91

Norephedrine Amphetamine

92 93

Amphetamine

94

•Mi'

trans-decahvdrnquinoline f

octahydrophenanthrene

'h NHR cyclohexane

HO. Norephedrine Norepinephrine

2-3

95, 96, 97

N-Isopropylnorephedrine

7

98

benzocycloheptene

-(CH )g. 2

[10]-paracyclophane


COMPUTER-ASSISTED

456

Table V

(cont'd.)

Ephedrine Isoproterenol

(0H)

DRUG DESIGN

I

2

1-2

99

NHR

R' chromane

8.

OH 100, 101

N-Methyldopamine

HO

NH

octahydrobenzo[f1quinoline

9-

(OH)

OCX 2

NHR £ t 2-aminotetralin R ^

102119

Phenylethylamine Dopamine Norepinephrine Epinephrine

NH

11.

Norephedrine Dopamine Norepinephrine Epinephrine

1

106 120127

tetrahydroisoquinoline R'

(OH),

NHR

Norephedrine Amphetamine Dopamine

103, 105, 123, 128130

2 - aminoindane Ph

12.

Amphetamine

NH

0

2

cyclopropane


129, 131133

21.

Analogs

GRUNEWALD E T A L .

Table V

Hi

(OH)

lk.

457

Methamphetamine

(cont'd.)

13.

NH

of

Norephedrine Amphetamine Dopamine Metaraminol

1-2

130, 132, 134, 135

Ephedrine

1

136

2

cyclobutane Ph / HN

~"Ύ\ u

OH R azetidine

Phenylethanolamine

15. NHR

Amphetamine Methamphet amine

137140

Amphetamine Methamphet-

130, 141144

benzonorbornene

16. NHR

a

m

i

n

e

b e n z o b i c y c l o [ 2 . 2 .2]]octene


COMPUTER-ASSISTED

458

DRUG DESIGN

i n h i b i t i o n o f dopamine uptake i n t o s t r i a t a l t i s s u e showed t h a t a gauche conformer (a-amino, e-phenyl) was c o n s i d e r a b l y more p o t e n t than t h e o t h e r t h r e e i s o m e r s . B l o c k a d e o f t h e uptake o f b i o g e n i c amines i n t o p l a t e l e t s by t h e f o u r amphetamine conformers showed l i t t l e s e l e c t i v i t y (the l e a s t p o t e n t isomer b e i n g 60% as e f f e c t i v e as t h e most p o t e n t ) . Amphetamine a n a l o g s i n s k e l e t o n 3 (£2,93) showed no amphetamine-like b e h a v i o r a l e f f e c t s and no amphetamine-like hyperthermia i n animals. This skeleton i s r i g i d , but shows some d i s t o r t i o n s from normal bond a n g l e s f o r a n t i p e r i p l a n a r and gauche c o n f o r m a t i o n s . S k e l e t o n s 4, 5, 7-11 13 and 14 have v a r y i n g degrees of c o n f o r m a t i o n a l f l e x i b i l i t y which make any c o n f o r m a t i o n - a c t i v i t y r e l a t i o n s h i p s d i f f i c u l t , i f not impossible, to obtain. S k e l e t o n 6 does n o t mimic any of t h e low-energy c o n f o r m a t i o n s o f t h e p h e n y l e t h y l amine s k e l e t o n . A l t h o u g h s k e l e t o n 12 has t h e fewest p o s s i b l e number o f e x t r a atoms (one e x t r a f o r a p h e n y l e t h y l a m i n e and none f o r an amphetamine) t h e bond a n g l e s a r e so d i s t o r t e d t h a t an extended c o n f o r m a t i o n cannot be a c h i e v e d by t h e t r a n s - s u b s t i t u t e d c y c l o p r o p y l system and a gauche conformer cannot be approximated (the c i s - i s o m e r i s a c t u a l l y an e c l i p s e d c o n f o r m e r ) . f

Choice of a Conformationally-Defined Analog In our s e a r c h f o r t h e most s u i t a b l e system f o r the s t u d y o f sympathomimetic amines, we chose i n i t i a l l y t o l o o k a t a system w i t h t h e minimum o f s y n t h e t i c problems i n o b t a i n i n g s u i t a b l e q u a n t i t i e s f o r i n i t i a l pharmacol o g i c a l evaluation. To t h i s end we chose t o l o o k a t amphetamine a n a l o g s , w i t h the u l t i m a t e aim o f a d d i n g t h e 3 - h y d r o x y l and c a t e c h o l h y d r o x y l s t o produce t h e c a t e c h o l a m i n e s . We f e l t t h a t i t was e s s e n t i a l t h a t the system chosen have a minimum number o f " e x t r a " atoms n o t p r e s e n t i n amphetamine (or i t s N-methyl d e r i v a t i v e , methamphetamine). I t was a l s o n e c e s s a r y t h a t the system n o t be h i g h l y s t r a i n e d and t h a t the bond a n g l e s and bond l e n g t h s found i n the low-energy c o n f o r m a t i o n s o f amphetamine be v e r y c l o s e l y a p p r o x i mated i n t h e c o n f o r m a t i o n a l l y - d e f i n e d model. I t was d e s i r e d t h a t any system chosen would show s i m i l a r p h y s i c a l p r o p e r t i e s t o t h o s e o f amphetamine — lipop h i l i c i t y ( p a r t i t i o n c o e f f i c i e n t ) , pKa and charge distribution in particular. Examination of these p o i n t s suggested s k e l e t o n s 15 and 16 o f T a b l e V. S i n c e the b e n z o b i c y c l o [ 2 . 2 . 1 ] heptene a n a l o g s ( s k e l e t o n 15) a r e c o n s i d e r a b l y more s t r a i n e d than t h e b e n z o b i c y c l o [ 2 . 2 . 2 ] o c t e n e ( s k e l e t o n


21.

GRUNEWALD E T A L .

Analogs

of

Methamphetamine

459

16), t h e l a t t e r was chosen f o r o u r i n i t i a l s t u d y . However, d e r i v a t i v e s o f s k e l e t o n 15 and i t s oxob r i d g e d a n a l o g , were a l s o p l a n n e d (see F i g u r e 7 ) . F i g u r e s 5 and 6 show t h e r e l a t i o n s h i p o f t h e methamphetamine o r amphetamine a n a l o g s i n s k e l e t o n 16 t o amphetamine and methamphetamine. The b e n z o b i c y c l o [ 2 . 2 . 2 ] o c t e n e system has o n l y t h r e e " e x t r a " atoms and thus appeared t o have a number o f advantages o v e r t h e o t h e r systems i n T a b l e V and F i g u r e 7. F i r s t , t h e two low-energy c o n f o r m a t i o n s o f the p h e n y l e t h y l a m i n e s c a n be c l e a r l y f i x e d (the systems a r e almost c o m p l e t e l y r i g i d , i n c o n t r a s t t o t h e more e x t e n s i v e l y - s t u d i e d systems l i k e s k e l e t o n s 9 and 13 o f Table V). Second, m o l e c u l a r models show t h e r e i s minimal d i s t o r t i o n i n bond a n g l e s o r bond l e n g t h s from t h o s e i n t h e m o b i l e system, amphetamine. T h i s i s n o t so f o r systems I I I - V I I I o f F i g u r e 7. T h i r d , a r e l a t i v e l y s i m p l e s y n t h e t i c p r o c e d u r e would a f f o r d b o t h the endo- and exp-isomers o f amphetamine (NH-N and NHX) o r methamphetamine (NM-N and NM-X) so t h e system c o u l d be e v a l u a t e d by x - r a y c r y s t a l l o g r a p h y t o d e t e r mine t h e p r e c i s e bond a n g l e s and bond l e n g t h s i n comparison t o t h o s e o f t h e m o b i l e (amphetamine) system. U s i n g t h e atomic c o o r d i n a t e s o f t h e x - r a y s t u d y , m o l e c u l a r o r b i t a l c a l c u l a t i o n s c o u l d be c a r r i e d o u t t o compare t h e r i g i d system w i t h t h e m o b i l e system (/i.e., charge d i s t r i b u t i o n s ) . And, most i m p o r t a n t l y , i t c o u l d be e v a l u a t e d p h a r m a c o l o g i c a l l y i n comparison w i t h t h e m o b i l e drug t o see i f c o n f o r m a t i o n a l d i f f e r e n c e s i n a c t i v i t y were p r e s e n t . Any d i f f e r e n c e s c o u l d then be i n t e r p r e t e d i n terms o f p r e c i s e c o n f o r m a t i o n a l arguments. To date t h e b e n z o b i c y c l o [ 2 . 2 . 2 ] o c t e n e system has l i v e d up t o i t s e x p e c t a t i o n s . I n t h e r e m a i n i n g p a r t o f t h i s d i s c u s s i o n we w i l l a d d r e s s the above p o i n t s . E v a l u a t i o n o f Some B i c y c l i c Systems as Conformationally-Defined Phenylethylamines. X-Ray Crystallography. Perhaps t h e u l t i m a t e t e s t o f t h e s u i t a b i l i t y o f a chemical s t r u c t u r e f o r preparing c o n f o r m a t i o n a l l y - d e f i n e d a n a l o g s would be t h e i r a b i l i t y t o produce b i o l o g i c a l e f f e c t s i d e n t i c a l t o t h o s e o f t h e p a r e n t compound. S i n c e t h i s i d e a l i s r a r e l y a c h i e v e d , and s i n c e a "wrong" conformer s h o u l d be i n a c t i v e , i t i s u s e f u l t o have o t h e r c r i t e r i a w i t h which t o e v a l u a t e t h e s e systems. The b i c y c l i c molec u l e s t o be examined i n t h e p r e s e n t s t u d y a r e compounds I - V I I I ( F i g u r e 7 ) , b e n z o b i c y c l o [ 2 . 2 . 2 ] o c t e n e s , benzob i c y c l o [2.2.1]heptenes, and 1 , 2 , 3 , 4 - t e t r a h y d r o - l , 4 epoxynaphthalenes. A number o f s t r u c t u r a l parameters



460

Ο

NH

2

r CH ,HMi

3

'gauche' amphetamine

'anti' amphetamine

o

NHR

Η

exo-analog NH-X (R = H) NM-X (R=CH ) 3

NHR endo-analog NH-N

(R=H)

NM-N (R=CH ) 3

Figure 5. Relationship of the exo- and endo-2-amino- and 2-methylaminobenzobicyclo[2.2.2]octenes to the two low energy conformations of amphetamine and methamphetamine. The abbreviations shown for the conformational^ defined analogs are used throughout the text.


GRUNEWALD E T A L .

Analogs

of

Methamphetamine

461

€13

Figure 6. ORTEP drawings of (a) amphetamine (146) drawn in the same perspective as that for (b) 2-methylaminobenzobicyclo[ 2.2.2 Joctene ( exo-isomer NM-X) and (c) endo-isomer NM-N (145).



462

ο 0

VII(OH-X) Figure 7.

"

1

Γ1

'2

VIII(OH-N)

Conformationally defined analogs of phenylethylamines (see text)


21.

GRUNEWALD E T A L .

Analogs of Methamphetamine

463

( d i h e d r a l a n g l e s , bond a n g l e s and i n t e r a t o m i c d i s t a n c e s ) can be determined f o r t h e s e b i c y c l i c p h e n y l e t h y l a m i n e a n a l o g s s i n c e t h e carbon s k e l e t o n s o f t h e s e compounds have almost no f l e x i b i l i t y . These s t r u c t u r a l parameters can be compared w i t h t h e c o r r e s p o n d i n g v a l u e s d e r i v e d from x - r a y s t r u c t u r e d e t e r m i n a t i o n s and molecular o r b i t a l c a l c u l a t i o n s of phenylethylamines. The d i h e d r a l a n g l e s τ.^, T , ' , T and τ ~ ( i l l u s t r a t e d on s t r u c t u r e s I - I V o f F i g u r e 7j c o r r e s p o n d t o t h o s e i n F i g u r e 2. The s i g n i f i c a n t bond a n g l e s ( 9 w 0 ^ and θ ) a r e d e f i n e d i n s t r u c t u r e s V-VII o f F i g u r e 7. I n t e r a t o m i c d i s t a n c e s between f u n c t i o n a l groups p r o v i d e a measure o f how a c c u r a t e l y t h e r i g i d s t r u c t u r e s approximate t h e s p a t i a l placement o f t h e s e groups as o b s e r v e d i n c o n f o r m a t i o n a l l y - m o b i l e p h e n y l ethylamines. The f u n c t i o n a l groups o f i n t e r e s t (shown on s t r u c t u r e V I I I ) i n c l u d e t h e n i t r o g e n atom, t h e oxygen atom on C-2, t h e a r o m a t i c oxygen s u b s t i t u e n t s and t h e a r o m a t i c r i n g . Determination o f these d i s t a n c e s and a n g l e s was based on x - r a y s t r u c t u r e d e t e r m i n a t i o n s o f compounds h a v i n g t h e b e n z o b i c y c l o [2.2.2]octene (145) o r b e n z o b i c y c l o [ 2 . 2 . 1 ] h e p t e n e (147) r i n g systems. Where n e c e s s a r y , e x t r a atoms were added, u s i n g s t a n d a r d bond l e n g t h s and a n g l e s (44). These c a l c u l a t i o n s were c a r r i e d o u t w i t h t h e computer programs QCLM/ICOORD and QCLM/COORD (made a v a i l a b l e t o us by t h e Quantum C h e m i s t r y Group a t t h e U n i v e r s i t y o f Kansas) which c a l c u l a t e bond l e n g t h s , bond a n g l e s , d i h e d r a l a n g l e s and i n t e r a t o m i c d i s t a n c e s from atomic coordinates. The p o s i t i o n o f t h e a r o m a t i c r i n g was r e p r e s e n t e d by t h e c e n t e r o f t h e r i n g (CR), which was d e t e r m i n e d by a v e r a g i n g t h e c o o r d i n a t e s o f t h e s i x carbon atoms which make up t h e r i n g . 2

f

2

The x - r a y s t r u c t u r e d e t e r m i n a t i o n s o f exo- and endo-2-methylamino-1,2,3,4-tetrahydro-l,4-ethanonapht h a l e n e h y d r o c h l o r i d e s (145) s e r v e d as t h e b a s i s f o r c a l c u l a t i o n s o f t h e b e n z o b i c y c l o [ 2 . 2 . 2 ] o c t e n e compounds (NM-X and NM-N). The b e n z o b i c y c l o [ 2 . 2 . 1 ] h e p t e n e and 1 , 2 , 3 , 4 - t e t r a h y d r o - l ,4-epoxynaphthalene systems were c o n s t r u c t e d from t h e c o o r d i n a t e d a t a f o r b e n z o b i c y c l o [ 2 . 2 . 1 ] h e p t e n e s y n - and - a n t i - b r o m o b e n z e n e s u l f o n a t e s (147). Positions f o r t h e exo and endo amino groups were s e l e c t e d by u s i n g a s t a n d a r d C-N bond l e n g t h w i t h t h e bond a n g l e s and d i h e d r a l a n g l e s c a l c u l a t e d from a c r y s t a l l o g r a p h i c study o f 2-exo-aminonorbornane-2-carboxylic a c i d (148). The d i h e d r a l a n g l e τ , d e s c r i b e s t h e r o t a t i o n o f the a r o m a t i c r i n g w i t h r e s p e c t t o t h e e t h y l a m i n e s i d e c h a i n (see F i g u r e s 2 and 7 ) . Compared w i t h v a l u e s found i n x - r a y s t u d i e s and m o l e c u l a r o r b i t a l c a l c u l a -


COMPUTER-ASSISTED

464

DRUG DESIGN

t i o n s , t h e benzobicyclo[2.2·1] compounds p r o v i d e a b e t t e r a p p r o x i m a t i o n o f t h i s a n g l e than do the benzo b i c y c l o [2.2.2] compounds. T h i s i s r e p r e s e n t e d g r a p h i c a l l y i n F i g u r e 8. V a l u e s o f τ, o b s e r v e d i n x - r a y s t u d i e s (see above) a r e d e p i c t e d a l o n g w i t h the r e s u l t p r e d i c t e d by m o l e c u l a r o r b i t a l (see T a b l e VII) c a l c u l a t i o n s (90°). Compounds I I I - V I I I form an a n g l e o f 6 9 ° , w h i l e t h e b i c y c l o [ 2 . 2 . 2 ] compounds form a 60° d i h e d r a l angle. The comparison of τ v a l u e s may be d i v i d e d i n t o two groups: t h o s e f o r extended conformers ( τ = 180°) and t h o s e f o r gauche conformers ( τ = 6 0 ° ) . Both groups a r e d e p i c t e d i n F i g u r e 9. The a n a l o g s h a v i n g an extended c o n f o r m a t i o n a l l g i v e τ v a l u e s w e l l w i t h i n t h e range o f o b s e r v e d v a l u e s f o r extended phenylethylamines: the exo-benzobicyclo[2.2.2]octene isomer g i v e s a n e a r l y i d e a l τ d i h e d r a l a n g l e (179°); the exo-[2.2.1] compounds a r e n e a r l y as good (176°) , w h i l e the a n t i - [ 2 . 2 . 1 ] compound forms an a n g l e o f 168°. The gauche conformers a r e more d i f f i c u l t t o e v a l u a t e , s i n c e observed τ values are a v a i l a b l e f o r only three gauche p h e n y l e t h y l a m i n e s . A l l four conformationallyd e f i n e d s t r u c t u r e s a r e w i t h i n 10° o f the o b s e r v e d and c a l c u l a t e d v a l u e s , as i l l u s t r a t e d i n F i g u r e 9. The endo- [2.2.1] s t r u c t u r e ( τ = 59°) most n e a r l y approximates t h e p r e d i c t e d v a l u e o f 60°. The endo[2.2.2] and syn-[2.2.1] compounds form a n g l e s o f 69° and 70°, r e s p e c t i v e l y . B u i l d i n g the C-2 oxygen atom i n t o t h e b i c y c l o [2.2.1] r i n g system s e r i o u s l y d i s t o r t s τ ~ , the O-C-C-N d i h e d r a l a n g l e . As shown i n F i g u r e 10, t h e benzo b i c y c l o [2 . 2 . 2 ] o c t e n e s p r o v i d e e x c e l l e n t v a l u e s f o r ~ (endo, 59°; exo, 56°), but V I I forms an 83° a n g l e . The endo isomer V I I I , which approximates an a n t i p e r i p l a n a r arrangement o f t h e oxygen and n i t r o g e n atoms, forms an a n g l e o f 160°, compared t o a p r e d i c t e d a n g l e o f 180°. The bond a n g l e s θ , , Θ , and θ p r o v i d e an i n d i c a t i o n o f t h e amount or r i n g s t r a i n i n the b i c y c l i c ring structures. I d e a l l y , Θ, and θ, s h o u l d be 120°; i n t h e [2.2.2] r i n g system, t h i s i s d i s t o r t e d by about 7 ° , and i n t h e [2.2.1] s t r u c t u r e s i t i s n e a r l y t w i c e as d i s t o r t e d (by about 1 2 ° ) . The C1 -C2-C1 a n g l e ( θ ) i s w i t h i n t h r e e degrees o f the i d e a l t e t r a h e d r a l a n g l e (109°) f o r compounds I , I I , I I I , IV, V I I and V I I I . ^ _y ~ * a n t i - [2.2.1] s t r u c t u r e s , however, have θ v a l u e s o f 100° and 96°, r e s p e c t i v e l y . The s p a t i a l arrangement o f f u n c t i o n a l groups would appear t o be p a r t i c u l a r l y i m p o r t a n t i n o r d e r f o r conf o r m a t i o n a l l y - r e s t r i c t e d analogs to e x h i b i t b i o l o g i c a l 2

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7.66

7.25

6.03

7.66

6.17

7.79

5.03

4.74

3.69

5.03

3.85

5.10

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V

VI

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VIII

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Compound

TABLE VI

4.33 4.33

5.80 4.32 5.80 4.32

5.83 5.83

3.31 3.31 3.72

3.09 3.82 2.85

3.84 5.09 5.52 4.53 5.09 3.84

5.49 5.51 7.15 6.34 7. 23 5.47 5.94 4.65 7.15 6.34 5.49 5.51

5.25 5.93

(a) R e f e r e n c e 38; (b) r e f e r e n c e 146. The a u t h o r s o f t h i s r e f e r e n c e r e p o r t τι v a l u e s o f 7 2 0 , 7 7 0 , 7 0 ° and 83° f o r i - i v , r e s p e c t i v e l y ; (c) r e f e r e n c e 42. The a u t h o r s r e p o r t a τ value of 56°. 2

2.39

5.08 6.02

6.28

3.78

2.87

3.95

5.76 5.54

6.85

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6.28

3.78

G

3.01

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3

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6.37 7.38

D

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470

C O M P U T E R - A S S I S T E D D R U G DESIGN

N u m b e r of observations

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Figure 12. Comparison of the distances from the nitrogen to the para-oxygen in some conformationally defined analogs of phenylethylamines with those found from x-ray crystallographic studies reported for phenylethylamines (see text)


21.

GRUNEWALD E T A L .

Analogs

of

Methamphetamine

471

e t h y l a m i n e s which have such a c o n f o r m a t i o n i n the c r y s t a l s t r u c t u r e , so comparisons a r e not p o s s i b l e i n this instance. The o b s e r v e d i n t e r a t o m i c d i s t a n c e from t h e c e n t e r of the a r o m a t i c r i n g t o t h e C2-oxygen atom (CR t o C2-0£ ranges from 3.53 t o 3.76 Â, w i t h a mean v a l u e o f 3.68 A. The b e n z o b i c y c l o [ 2 . 2 . 2 ] o c t e n e system g i v e s a r e a s o n a b l y good CR t o C2-0 d i s t a n c e (3.78 A ) . As might be e x p e c t e d , compounds V I I and V I I I , i n which t h e oxygen atom i s b u i l t i n t o a somewhat s t r a i n e d s t r u c t u r e , p r o v i d e a much l e s s a c c u r a t e CR t o C2-0 d i s t a n c e , 3.31 Â. In g e n e r a l , t h e b e n z o b i c y c l o [ 2 . 2 . 2 ] o c t e n e r i n g system a f f o r d s t h e b e s t model o f gauche and extended phenylethylamine conformers. I t s main drawback would appear t o be t h e s l i g h t l y low v a l u e o f τ·^. The exo and e n d o - b e n z o b i c y c l o [ 2 . 2 . 1 ] h e p t e n e s ( s t r u c t u r e s I I I and IV)and t h e 1,2,3,4-tetrahydro-l,4-epoxynaphthalenes (VII and V I I I ) p r o v i d e m o d e r a t e l y good a p p r o x i m a t i o n s of p h e n y l e t h y l a m i n e c o n f o r m a t i o n s , a l t h o u g h t h e p l a c e ment o f t h e C2-oxygen atom i s somewhat d i s t o r t e d i n s t r u c t u r e s V I I and V I I I . The s y n - and a n t i - b e n z o b i c y c l o [ 2 . 2 . 1 ] h e p t e n e s (V and VI) seem t o be t h e l e a s t s u i t a b l e o f the s t r u c t u r e s s t u d i e d ; d i h e d r a l a n g l e s , bond a n g l e s and i n t e r a t o m i c d i s t a n c e s d i f f e r s u b s t a n t i a l l y from p r e d i c t e d and o b s e r v e d v a l u e s . A l l t h i n g s c o n s i d e r e d , the b e s t systems appear t o be I and I I (NM-X and NM-N f o r methamphetamine a n a l o g s ) . E v a l u a t i o n o f Some B i c y c l i c Systems as Conformationally-Defined Phenylethylamines. CNDO/2 C a l c u l a t i o n s on Amphetamines. Quantum m e c h a n i c a l s t u d i e s on p h e n y l e t h y l a m i n e and amphetamine have been c a r r i e d o u t p r e v i o u s l y by Pullman and coworkers (59,67) u s i n g b o t h t h e s e m i - e m p i r i c a l PCILO and an ab i n i t i o method, and by H a l l and coworkers (71) u s i n g an ab i n i t i o method. The r e s u l t s o f t h e s e two groups were quite simi1ar. Our aim b e i n g t o i n v e s t i g a t e b o t h t h e energy d i f f e r e n c e s and t h e charge d i s t r i b u t i o n s o f a v a r i e t y of p h e n y l e t h y l a m i n e s , we chose the CNDO/2 method o f P o p l e kown In VIQUKZ 13, not TlguKo, 2 ) : 5

z

and τ 7 ( C - N C -C ) ? (The uèual c o n v e n t i o n f o r t o r s i o n a n g l e s was f o l l o w e d : t h u s , τ, i s t h e a n g l e between t h e p l a n e s t h r o u g h C.C C ana C C C . The a n g l e i s p o s i t i v e f o r c l o c k w i s e r o t a t i o n s about 6 ~ 7 l o o k i n g from C t o C-). When Ν i s u n s u b s t i t u t e d , thé energy i s n e a r l y indépendent o f τ- (71.) / and so i t i s ignored. When " 2 5 ( 9 1 3 ) , τ - must be chosen with care, but reasonable values f o r are readily found from an e x a m i n a t i o n o f m o l e c u l a r models, and were v e r i f i e d by a m i n i m a l number o f t r i a l c a l c u l a t i o n s . Energy s u r f a c e s f o r amphetamine and N-ethylamphetamine have been p l o t t e d i n t h e c o n v e n t i o n a l way as f u n c t i o n s o f τ, and τ ( F i g u r e s 14 and 15). I n a d d i t i o n , t h e v a r i a t i o n o f t h e energy s u r f a c e o f Nethylamphetamine as a f u n c t i o n o f τ and τ i s presented (Figure 16). Because o f t h e r i n g symmetry, t h e maps o f amphet amine and N-ethylamphetamine ( F i g u r e s 14 and 15) a r e p e r i o d i c i n T ^ , w i t h p e r i o d 180°. The energy map o f amphetamine i s p r e s e n t e d i n F i g u r e 14. R o t a t i o n s were c a r r i e d o u t about τ, and τ i n a p p r o x i m a t e l y 30° i n c r e m e n t s , p o i n t s b e i n g added t o t h e b a s i c g r i d where i t was thought n e c e s s a r y , p a r t i c u l a r l y i n t h e a r e a 80°

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