Stereoisomeric Probes of the Dopamine Receptor - American

10 Stereoisomeric Probes of the Dopamine Receptor C A R L KAISER

Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: June 29, 1983 | doi: 10.1021/bk-1983-0224.ch010

Smith Kline & French Laboratories, Research and Development Division, Philadelphia, PA 19101

Enantiomers o f v a r i o u s dopaminergic agents have been utilized to complement s t r u c t u r e - a c t i v i t y s t u d i e s t o examine dopamine r e c e p t o r s . O p t i c a l antipodes are p a r t i c u l a r l y u s e f u l in such s t u d i e s as t h e i r identical p h y s i c a l p r o p e r t i e s assure that t h e i r pharmacological a c t i o n s are likely due t o receptor i n t e r a c t i o n s , unless they are metabolized d i f f e r e n t l y . In the present i n v e s t i g a t i o n enantiomers of 2,3,4,5-tetrahydro7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SK&F 38393), the 6-chloro-4'-hydroxy d e r i v a t i v e (SK&F 82526) and its 3-allyl congener (SK&F 85174) were separated. Optical p u r i t y was determined by NMR and HPLC methods. Absolute stereochemistry was e s t a b l i s h e d by s i n g l e - c r y s t a l x-ray d i f f r a c t o m e t r i c a n a l y s i s and CD s p e c t r a l methods. Dopamine-like activity was determined in s e v e r a l in vitro and in vivo t e s t s . In c e r t a i n cases a h i g h degree of e n a n t i o s e l e c t i v i t y was observed. In an attempt to r a t i o n a l i z e the observed enantioselectivity, 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 , conformat i o n a l and c o n f i g u r a t i o n a l aspects of the benzazepines were compared to those of c e r t a i n other dopamine r e ceptor agonists and antagonists. Comparison of the benzazepines w i t h v a r i o u s receptor models derived from other dopamine agonists/antagonists, permits r a t i o n a l i z a t i o n o f t h e i r e n a n t i o s e l e c t i v i t y . The 1-phenyl subs t i t u e n t in the benzazepines apparently binds to an accessory lipophilic s i t e ; however, p r e c i s e l o c a t i o n of t h i s region was not p o s s i b l e . I t is suggested that the mode of binding of the benzazepines may differ somewhat from that of many other dopamine receptor antagonists and a g o n i s t s . Conceivably, the d i f f e r e n t o v e r a l l conformations of agents of t h i s c l a s s may a c count f o r their mixed agonist-antagonist activities.

0097-6156/83/0224-0223$07.00/0 © 1983 American Chemical Society In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


224

DOPAMINE

RECEPTORS

The r e c o g n i t i o n that dopamine (DA) i s an important neurot r a n s m i t t e r w i t h receptors i n both the c e n t r a l nervous system and i n the periphery has r e s u l t e d i n a widespread search f o r substances that e i t h e r mimic or block the a c t i o n of t h i s n a t u r a l neurotransmitter on i t s r e c e p t o r s . T h i s has r e s u l t e d i n the d i s c o v e r y of an enormous number of compounds of d i v e r s e s t r u c ture that have DA receptor agonist and antagonist p r o p e r t i e s . In many, but not a l l , instances i t has been p o s s i b l e to r e l a t e the s t r u c t u r e of these compounds to that of DA, g e n e r a l l y i n a trans ( a n t i p e r i p l a n a r , extended) conformation i n which i t s s a l t i s found i n the s o l i d s t a t e ( 1 ) . Discovery of the DA-like a c t i v i t y of 2,3,4,5-tetrahydro-7, 8-dihydroxy-l-phenyl-lH-3-benzazepine ( I , SK&F 38393) (2,, 3) was of i n t e r e s t f o r s e v e r a l reasons. F i r s t l y , u n l i k e many other DA receptor modulators, conformational c o n s t r a i n t s imposed on t h i s molecule by v i r t u e of the tetrahydroazepine r i n g system prevent the embodied DA framework from a t t a i n i n g a f u l l y extended conformation. In a d d i t i o n , t h i s agent has a unique b i o l o g i c a l prof i l e suggesting s e l e c t i v i t y f o r the adenylate c y c l a s e modulated D - l (4_) subpopulation of DA r e c e p t o r s . A l s o , i t a c t s as a mixed agonist-antagonist i n i t s a b i l i t y to stimulate c e n t r a l DA-sensit i v e adenylate c y c l a s e . These observations l e d to an extensive examination of compounds r e l a t e d to I i n an e f f o r t to i d e n t i f y not only new s e l e c t i v e DA receptor agonists (_5), but a l s o antago n i s t s . As a consequence of t h i s study 3-benzazepine r e l a t i v e s of I w i t h s e l e c t i v i t y f o r p e r i p h e r a l DA receptors ( 6 ) , as w e l l as some new antagonists (7), were discovered. Several unique p e r i p h e r a l l y a c t i n g DA receptor a g o n i s t s , namely I I (SK&F 82526) and I I I (SK&F 85174), have been the subject of d e t a i l e d pharmac o l o g i c a l examination (8-12). 6-Chloro-2,3,4,5-tetrahydro-7,8dihydroxy-l-(4-hydroxyphenyl)-lH-3-benzazepine ( I I ) i s presentl y being studied i n the c l i n i c ( 9 ) . I, R = X = H; Ar = C H 6

5

I I , R = H; X = CI; Ar = 4-HOC H 6

4

I I I , R = CH CH=CH ; X = CI; Ar = 4-HOC H 2

2

6

4

IV, R = X = Ar = H 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 (SAR) s t u d i e s i n t h i s ser i e s of tetrahydrobenzazepines (5) i n d i c a t e that the 1-phenyl, or s u b s t i t u t e d phenyl, group c o n t r i b u t e s s i g n i f i c a n t l y to the DA receptor agonist p r o p e r t i e s of these compounds (13, 14). As the 1-phenyl substituent i n I - I I I provides these molecules with an asymmetric center, separation and study of the enantiomers was of p a r t i c u l a r i n t e r e s t . Enantiomers of both DA receptor agonists (e.g., 15-19) and

In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

10.

KAISER

Stereoisomeric

225

Probes


antagonists (e.g., 20-29) have uniformly demonstrated enantios e l e c t i v i t y . These f i n d i n g s have been employed to complement SAR observations i n probing the pharmacophores, t h e i r mode of i n t e r a c t i o n with DA receptors and, i n t u r n , to provide informat i o n r e l e v a n t to the topography of the r e c e p t o r s . As enantiomeric p a i r s have i d e n t i c a l p h y s i c a l p r o p e r t i e s , i f i t i s assumed that the isomers are metabolized i d e n t i c a l l y , b i o l o g i c a l d i f ferences (30-33) may reasonably be a s s o c i a t e d with receptor r e l a t e d events (34). These c o n s i d e r a t i o n s , coupled w i t h the pharmacological and chemical uniqueness of the tetrahydrobenzazepines I - I I I , suggested examination of t h e i r o p t i c a l antipodes f o r DA-like a c t i v i t y . Chemistry I n i t i a l l y , the racemates of I - I I I were not e a s i l y separable by r e c r y s t a l l i z a t i o n of d i a s t e r e o i s o m e r i c s a l t s with o p t i c a l l y a c t i v e a c i d s ; however, methylated precursors (V a,b and VI a,b) were e a s i l y resolved v i a t h e i r d i b e n z o y l t a r t r a t e s (35, 36). Conversion of these precursors to the o p t i c a l antipodes of I - I I I was performed as i l l u s t r a t e d i n Scheme I (35, 36). Absolute stereochemistry of the enantiomers of I was est a b l i s h e d by s i n g l e - c r y s t a l x-ray d i f f r a c t o m e t r i c a n a l y s i s of (R)-I»HC1 (J37), as w e l l as by s i m i l a r a n a l y s i s of (R)-Va«CH I which was subsequently converted to (R)-I v i a a s t e r e o s p e c i f i c s y n t h e t i c sequence (35). Computer generated p e r s p e c t i v e drawings (38) of two rotamers of the isomer [[ot]j)-> + 15.3° ( 1, CH3OH)] observed i n the x-ray a n a l y s i s are shown i n Figure 1. The l o c a t i o n of the hydrogen i n p o s i t i o n 1 i s i n c l u d e d f o r c l a r i t y . The absolute c o n f i g u r a t i o n s of (R) and (S_)-II and I I I were assigned on the b a s i s of comparison of t h e i r c i r c u l a r dichroism s p e c t r a with those of (R) and ( S ) - I of known stereochemistry (36). Subsequently, the absolute stereochemistry of (R)~ I I H B r was confirmed by s i n g l e - c r y s t a l x-ray d i f f r a c t o m e t r i c a n a l y s i s (39). O p t i c a l p u r i t i e s of the enantiomers of I - I I were d e t e r mined by high performance l i q u i d chromatographic a n a l y s i s of t h e i r amides with (-)-Ofc-methoxy-Ofr-trifluoromethylphenyl-acetic a c i d . The o p t i c a l p u r i t y of (R) and ( S J - I I I was estimated by NMR d i f f e r e n t i a t i o n of methoxyl s i g n a l s of i t s precursor VII i n the presence of a c h i r a l s h i f t reagent (36). In a l l i n s t a n c e s enant i o m e r i c excesses were shown to be about 90% or g r e a t e r (35_, 36). 3

c

#

Pharmacology of (R) and

(J5)-I-III

As i n d i c a t e d i n Table I , I - I I I and t h e i r R and S_ o p t i c a l antipodes were studied f o r dopaminergic a c t i v i t y i n f o u r primary tests: (1) s t i m u l a t i o n of c e n t r a l DA-sensitive adenylate cyc l a s e (2^, 35), (2) displacement of [ % ] - s p i r o p e r i d o l binding to r a t caudate homogenate (35, 40) , (3) i n d u c t i o n of r o t a t i o n s i n r a t s with u n i l a t e r a l l e s i o n s of the l e f t s u b s t a n t i a n i g r a (2^,


DOPAMINE

226

RECEPTORS

NCH. CH 0 3

Ph-4-Y

Ph-4-Y VI

a, X = Y = H b, Χ = C l ; Y = OCH


3

1.

0.5 mol (+) o r (-) dibenzoyltartaric acid

1 mol (+) o r (-) dibenzoyltartaric acid

2.

Recrystn. MeOH o r aq. MeOH

Recrystn. MeOH o r aq. MeOH Cl

(R) and (S)-V 1. BrCN 2. HC1, H 0

1

2

NCH CH=CH 2

(R) and (S)-VI h-4-0CH

Methionine CH3SO3H or BBr

(R) and (j>)-VII

3

Methionine CH3SO3H or

(R) and ( S ) - I , I I

BBr

3

(R) and ( S ) - I I I Scheme I

35), and (4) reduction of r e n a l v a s c u l a r r e s i s t a n c e (RVR) i n dogs (6^). Potency i n the adenylate c y c l a s e t e s t [a D-l r e c e p t o r r e sponse (4^)] i s expressed i n terms of an EC50, the molar con c e n t r a t i o n of compound that produces h a l f maximal s t i m u l a t i o n o f cyclic-AMP production. T h i s maximum (% o f maximum DA response) and the c o n c e n t r a t i o n a t which i t i s observed are a l s o g i v e n . S p i r o p e r i d o l binding [a c e n t r a l DA response i n v o l v i n g D-2 r e ceptors (41)] e f f e c t i v e n e s s i s presented as an 1050, i . e . , the c o n c e n t r a t i o n of compound causing 50% i n h i b i t i o n of s p e c i f i c s p i r o p e r i d o l binding. R o t a t i o n i n r a t s w i t h l e s i o n s i n the s u b s t a n t i a l n i g r a ( a s u p e r s e n s i t i v e DA receptor response) i s quantitated by a RD500 value which i s defined as the dose of


2


KAISER

Stereoisomeric

Probes

227

Figure 1. Computer-generated perspective drawing of two rotamers (Λ,B). (See text for discussion) (37, 38j. Key: O , carbon; Φ, nitrogen; ®, oxygen; and ®, hydrogen.


DOPAMINE

228

RECEPTORS

compound c a l c u l a t e d to produce 500 b o d i l y r o t a t i o n s during a 2 hour t e s t p e r i o d . Renal v a s o d i l a t o r potency (presumably a p e r i p h e r a l DA receptor agonist a c t i o n ) i s expressed as ED15 and ED20 values, the average maximum cumulative dose that decreases RVR by 15% and 20%, r e s p e c t i v e l y . The maximum observed decrease i n RVR and the cumulative dose producing t h i s e f f e c t are a l s o presented.


S trueture-Activity Relationship

Considerations

The data presented i n Table I i n d i c a t e that a p r o p e r l y o r i ented 1-phenyl substituent i s important f o r DA receptor a c t i v a t i o n by 2,3,4,5-tetrahydro-7,8-dihydroxy-lH-3-benzazepines. Thus, i n the t e s t f o r s t i m u l a t i o n of DA-sensitive adenylate cyc l a s e the R isomers, as w e l l as the racemates of I - I I I are cons i d e r a b l y more potent than the parent IV which l a c k s a s u b s t i t u ent i n the 1 p o s i t i o n . The EC50 of IV i s 5.2 \M (35); i . e . , i t i s two orders of magnitude l e s s potent than I i n t h i s system (see Table I ) (13). Likewise, IV was 5 - f o l d l e s s e f f e c t i v e i n causing c o n t r a l a t e r a l r o t a t i o n s i n r a t s with l e s i o n s i n the subs t a n t i a n i g r a when the compounds were administered d i r e c t l y i n t o the i p s i l a t e r a l striatum. The RD50O f o r I was 0.18 iJg/rat as compared to 0.9 IJg/rat f o r IV (14). I t a l s o appears that the 6-C1 s u b s t i t u e n t enhances binding at the receptor. Although complicated by d i f f e r e n c e s i n the substituents i n p o s i t i o n s 1 and 3, the observation that racemic I I and I I I are more potent than I as stimulants of r a t s t r i a t a l adenylate c y c l a s e i s sugg e s t i v e of potency enhancement by v i r t u e of 6-C1 s u b s t i t u t i o n . T h i s suggestion i s supported by the 8 - f o l d enhancement of the potency of I i n t h i s t e s t upon i n t r o d u c t i o n of a 6-C1 s u b s t i t u ent ( 6 ) . The consequence of the 4 -0H substituent on receptor a c t i v a t i o n i s l e s s c l e a r . Thus, 4 - h y d r o x y l a t i o n of racemic I r e s u l t s i n an approximately 10-fold decrease i n potency i n the adenylate c y c l a s e assay and the observation (Table I) that (R*_S)~ I I i s only s l i g h t l y more potent than I i n t h i s t e s t i s c o n s i s tent w i t h a negative c o n t r i b u t i o n from the 4'-OH substituent. In c o n t r a s t , racemic I I i s nearly two orders of magnitude more potent than I as a r e n a l v a s o d i l a t o r i n dogs. Although s e v e r a l r a t i o n a l i z a t i o n s might be advanced f o r t h i s f i n d i n g , i t i s poss i b l e that the 4 -0H s u b s t i t u e n t increases the o v e r a l l p o l a r i t y of the molecule to hinder i t s accumulation i n l i p o p h i l i c s i t e s with a r e s u l t a n t elevated c o n c e n t r a t i o n i n the kidney (6). The p e r i p h e r a l s e l e c t i v i t y of the 4'-OH d e r i v a t i v e s I I and I I I i s evidenced by t h e i r e f f e c t i v e n e s s i n the dog r e n a l v a s o d i l a t o r t e s t f o l l o w i n g i v a d m i n i s t r a t i o n whereas they are i n e f f e c t i v e i n the l e s i o n e d r a t r o t a t i o n a l model f o l l o w i n g i p dosing. These r e s u l t s suggest that these compounds are unable to penetrate the l i p o p h i l i c "blood-brain b a r r i e r " to enter i n t o the b r a i n . T h i s s u p p o s i t i o n i s supported by the demonstration that I I i s q u i t e potent (about o n e - f i f t h as potent as DA) i n t h i s t e s t when i t i s given i n t r a c a u d a l l y ( 6 ) . f

1

f


10.

KAISER

Stereoisomeric Probes

229

Table I . Dopaminergic A c t i v i t y of I - I I I and Enantiomers£

Adenylate cyclase t c-AMP, E C , UM,J1>£ [max + ,É % a t concn, UM] 5 0

Compound


(R,S)-ie

Spiroperidol binding I C

50» VJM£»£

Renal vasodilat o r , dogs, Rotation i n lesioned r a t , ED ,1 Ug/kg, RD500.i'£ mg/kg, i p o r i v (max Ψ RVR, cum. [rotations, dose) mg/kg, i p ]

0.071 (0.052-0.106) [68,10]

0.7 34.43 (33.42-41.91) (0.0-1.0)

ED =3ll (19,110)

0.032 (0.02-0.05) [66,10]

0.5 33.86 (28.56-40.14) (0.33-0.71)

ED =25 (18,40)

[50+8,2.0]!. 197.4 (151.7-257.0)

(9,550)

(S)-ie

l 5

15

[27,1. 100] [14+7,10]]!

EDx5=0.3 ED =0.8 (50,5300)

0.057 (0.031-0.096) [68,1.0]

1.03 (0.9-1.17)

0.037 (0.022-0.064) [73,10]

0.54 (0.48-0.60)

i

1.47 (0.79-2.7) [44,10]

18.2 (16.0-21.0)

i_

(R,j>)-III

0.015 (0.01-0.021) [85,1.0]

[647+84,10] 0.152 (0.132-0.176)

(R)-III

0.0088 (0.005-0.013) [80,1.0]

0.106 (0.086-0.129)

i_

(S)-III

[18,1. 10]

15.3 (13.3-17.5)

i

ED =4.4l (19,20)

DAË.

3.5 [100,45]

5.34 (4.18-6.82)

1

ED =2.7 ED =5.0 (43,100)

(R,S)-II

(R)-H

(S)-II

20

ED =0.31 ED 0=0.42 (48,1500) 15

2

ED =0.94 ED =6.67 (38,530) 15

20

ED =21.82 (29,170) 20

ED o=0.75 (51,20) 2

l5

15

20

Continued

on n e x t


page.

230

DOPAMINE

RECEPTORS


Footnotes to Table I . — A l l compounds were t e s t e d as CH3SO3H s a l t s unless otherwise noted. See t e x t f o r references to t e s t systems, EC, ED, RD and IC values. £ 95% confidence l i m i t s i n paren theses. iL Percent of cyclic-AMP induced by 5 χ 10"5 M DA. *L HC1 s a l t . L I n s u f f i c i e n t l y potent f o r determination of ED20 value. S. I n s u f f i c i e n t l y potent f o r determination of EC, RD or ED values. Jl RD500 • 0.5 (0.4-0.8) Ug/rat, i . e . L Not t e s t e d . J. Value not a v a i l a b l e ; i n a b i l i t y of DA to enter CNS a f t e r i p a d m i n i s t r a t i o n r e q u i r e s use of DOPA and D0PA decarboxylase i n h i b i t o r (_36) ; RD500 = 0.10 (0.08 - 1.3) Ug/rat, i . e .

I n t r o d u c t i o n of an a l l y l group i n t o p o s i t i o n 3 of I and I I apparently has l i t t l e e f f e c t , or s l i g h t l y i n c r e a s e s , potency as stimulants of DA-sensitive adenylate c y c l a s e . I and i t s N - a l l y l d e r i v a t i v e (EC50 ca. 0.065 iM) are about equipotent i n t h i s t e s t whereas racemic I I I i s almost 4 - f o l d more potent than race mic I I . N - A l l y l s u b s t i t u t i o n of I I , however, seems to modify the o v e r a l l DA receptor agonist p r o f i l e of the molecule. Com p a r i s o n of the data f o r I I and I I I i n the adenylate c y c l a s e and s p i r o p e r i d o l t e s t s shows that I I i s about 18 times more potent i n the adenylate c y c l a s e (D-1) t e s t than i n d i s p l a c i n g bound s p i r o p e r i d o l (D-2) (41) whereas I I I i s only 10 times more e f f e c t i v e . T h i s may suggest that N - a l l y l a t i o n r e s u l t s i n m o d i f i c a t i o n of the a f f i n i t y of the agents f o r subtypes of DA recep t o r s . Indeed, secondary pharmacological studies i n d i c a t e that the mechanism of a c t i o n of I I I i n c l u d e s a presynaptic dopaminer g i c component (10). The p o s s i b i l i t y that I I and I I I may have d i f f e r e n t e f f e c t s on various receptors may a l s o account f o r the d i f f e r e n c e s i n potency and o v e r a l l c a r d i o v a s c u l a r p r o f i l e s (39, 42) of these two compounds i n the dog r e n a l v a s o d i l a t o r t e s t . In summary, the r e s u l t s of SAR s t u d i e s suggest that sub s t i t u t i o n of p o s i t i o n s 3, 6 and 4* i n f l u e n c e the potency, s e l e c t i v i t y and even the mechanism of a c t i o n of 2,3,4,5-tetrahydro7,8-dihydroxy-lIT-3-benzazepines as DA receptor a g o n i s t s . C o n f i g u r a t i o n a l Considerations. In general, the data tab u l a t e d i n Table I i n d i c a t e e n a n t i o s e l e c t i v i t y f o r the benzaze p i n e s I - I I I . DA receptor agonist a c t i v i t y r e s i d e s mainly i n the R isomers; however, the R:S_potency r a t i o s vary c o n s i d e r a b l y de pending upon the p a r t i c u l a r t e s t system. In some instances the S_ isomers are q u i t e e f f e c t i v e . T h i s i s p a r t i c u l a r l y notable f o r I I and I I I i n the t e s t f o r r e n a l v a s o d i l a t o r a c t i v i t y i n dogs. Comparison of the ED]^ and ED20 values f o r (R) and ( S ) - I I provides potency r a t i o s of 3 and 15.9, r e s p e c t i v e l y , and both isomers are somewhat more potent than I . Likewise, both (R) and ( S ) - I I I have a high degree of r e n a l v a s o d i l a t o r a c t i v i t y i n



10.

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Stereoisomeric

Probes

231

anesthetized dogs. The reason f o r decreased e n a n t i o s e l e c t i v i t y of I I and I I I i n t h i s i n v i v o t e s t i s not known. Perhaps i t i s r e f l e c t i v e of an a l t e r e d e f f e c t of the isomers on d i f f e r e n t or m u l t i p l e r e c e p t o r s . T h i s i s c o n s i s t e n t with the o b s e r v a t i o n that the o v e r a l l c a r d i o v a s c u l a r p r o f i l e s of the enantiomers of I I (42) and I I I (39) are s i g n i f i c a n t l y d i f f e r e n t . Another sug g e s t i o n that the o v e r a l l mechanisms of a c t i o n of the enantiomers of I I I may d i f f e r d e r i v e s from the observation that racemic I I I i s 3 0 - f o l d l e s s potent than i t s R enantiomer. Perhaps (J3)-III i n t e r f e r e s with the r e n a l v a s o d i l a t o r e f f i c a c y of ( R ) - I I I . Ap p a r e n t l y , however, t h i s i s not the case f o r ( S ) - I I . ( R ) - I I i s about equipotent with the racemate. The comparatively weak po tency of (j>)-III r e l a t i v e to that of (j>)-H i n the adenylate cy c l a s e and dog r e n a l v a s o d i l a t o r t e s t s may suggest that the D - l receptor may be able to accommodate both antipodes of I I , a l though the S_ f i t s l e s s r e a d i l y than the II isomer. The r e l a t i v e i n e f f e c t i v e n e s s of (j>)-III may i n d i c a t e that the N - a l l y l group of t h i s antipode i n t e r f e r e s with D - l receptor i n t e r a c t i o n . This o b s e r v a t i o n should be considered i n models f o r D-l r e c e p t o r s . I t appears of no s i g n i f i c a n c e i n the s p i r o p e r i d o l displacement t e s t where (j>)-II and ( S ) - I I I are approximately equipotent. Thus the N - a l l y l group may be accommodated i n D-2 receptors (36), which may t o l e r a t e g r e a t e r bulk i n the v i c i n i t y of the basic N. Conformational Considerations. A great d e a l of a t t e n t i o n has been d i r e c t e d toward the mode of i n t e r a c t i o n of DA with i t s r e c e p t o r s . As a consequence of the multitude of conformations that DA can a t t a i n because of i t s f l e x i b l e aminoethyl c h a i n , many s t u d i e s have been aimed toward more r i g i d , conformationally r e s t r i c t e d analogs (e.g., 43-48). These s t u d i e s have l e d to the g e n e r a l c o n c l u s i o n that a n e a r l y f u l l y extended trans ( a n t i p e r i planar) conformation of the DA, as i l l u s t r a t e d i n the Newman p r o j e c t i o n V I I I , i s required f o r both agonists (15) and antago n i s t s (49) of the receptor. I t has been suggested that DA may i n t e r a c t w i t h i t s receptors i n two rotameric extremes, the soc a l l e d α and 8 forms (43_, 44). Several dihydroxyoctahydrob e n z o [ f ] q u i n o l i n e s are noteworthy because they r i g i d l y f i x the c a t e c h o l i c system and the b a s i c N, two groups g e n e r a l l y acknow ledged to be c r i t i c a l f o r receptor i n t e r a c t i o n , i n a s t e r i c r e l a t i o n s h i p simulating the ot- and 8-rotameric forms. Thus, 7, 8-dihydroxyoctahydrobenzo[fJquinoline (IX) (45) c l o s e l y ap proximates the α conformer of DA and the 8,9-dihydroxy isomer (46) simulates the 8-form. The trans isomers are very r i g i d planar molecules whereas the c i s isomers are capable of f l i p ( t r a n s and gauche) conformations. Only the trans isomer of IX causes potent c e n t r a l and p e r i p h e r a l dopaminergic a c t i o n s (45). The trans isomer of X, however, produces only potent p e r i p h e r a l , but not c e n t r a l , DA-like e f f e c t s (46). The d i s t a n c e between the OH group "meta" to the ethylamine c h a i n and the b a s i c Ν i s 6.4 A



232

DOPAMINE

RECEPTORS

i n IX (as i t i s i n apomorphine). In X t h i s d i s t a n c e i s approxi mately 7.3 A. I t has been suggested t h i s s p a t i a l d i f f e r e n c e may e x p l a i n the v a r i a t i o n s i n r e a c t i v i t y of the compounds with DA receptor subtypes (46). S e v e r a l s t u d i e s with somewhat more f l e x i b l e aminotetralins approximating the α and 8 rotameric forms of DA have suggested that these conformations may account f o r d i f f e r e n c e s i n a c t i v i t y i n p a r t i c u l a r pharmacological models (47, 50, 51). Despite these observations, d e r i v a t i o n of a gen e r a l c o n c l u s i o n has not been p o s s i b l e because c l a s s e s of com pounds simulating both the a- and 8- conformers of DA c l e a r l y c o n t a i n potent DA receptor agonists (47, 52). A recent com prehensive study of the b e h a v i o r a l e f f e c t s of many r i g i d DA ana logs suggests that d e f i n i t i o n of the p r e f e r r e d rotameric confor mation f o r dopaminergic a c t i v i t y may be an " i l l u s o r y quest" (53). A f i n a l conformational p o i n t to be addressed i s the r e l a t i o n s h i p of the c a t e c h o l r i n g to the ethylamine chain; i . e . , whether the r i n g i s perpendicular to or planar w i t h the c h a i n . The poten t i a l energy d i f f e r e n c e between these rotameric forms i s s m a l l . Molecular o r b i t a l s t u d i e s and c r y s t a l l o g r a p h i c a n a l y s i s i n d i c a t e that the perpendicular form i s p r e f e r r e d (54, 55). The a c t i v i t y of the r i g i d analogs of DA, however, suggest that a coplanar a r rangement i s important. OH

VIII

IX

X

The conformation of I - I I I i s u n l i k e that of most other DA receptor agonists. As a r e s u l t of the conformational r e s t r a i n t s imposed by the tetrahydroazepine r i n g the DA skeleton w i t h i n these compounds i s unable to a t t a i n the extended form of DA ( V I I I ) . Nevertheless, the tetrahydroazepine r i n g of I - I I I does permit considerable conformational f l e x i b i l i t y ; the DA framework i n I - I I I can vary from a n e a r l y f o l d e d ( f u l l y e c l i p s e d , c i s ) o r i e n t a t i o n XI to a more extended p a r t i a l l y e c l i p s e d ( a n t i c l i n a l ) conformation XII. The observation that r i g i d molecules, e.g., s e v e r a l t e t r a h y d r o i s o q u i n o l i n e s , such as (-)-l,2-dihydroxyapor phine (56) and ( S _ ) - s a l s o l i n o l (57) , that incorporate a DA frame work i n a r i g i d l y f i x e d c i s o r i e n t a t i o n of the c a t e c h o l r i n g and b a s i c Ν l a c k DA receptor agonist a c t i v i t y points to the more ex tended conformation XII of I - I I I as the one most l i k e l y to be i n v o l v e d i n an i n t e r a c t i o n with the receptor. In t h i s conforma t i o n the distance between e i t h e r of the c a t e c h o l i c OHs, both of


Stereoisomeric

KAISER

10.

which seem necessary Ν i s about 7.0 A. OH

233

Probes

f o r D-1

receptor agonist a c t i v i t y , and OH HO ^ Ji X

the

N-R

H Ή Y


Y' a_, Χ = Y = R = H

b, X = C l , Y

ç_, X = C l , Y = OH, R = CH CH=CH 2

OH,

R = H

2

Discussion Most DA receptor agonists can be c a t e g o r i z e d (58) as (1) phenethylamines (e.g., 59, 60, 61), (2) aporphines (e.g., 62-65) , (3) a m i n o t e t r a l i n s (e.g., 66-70), (4) aminoindans (e.g., 71-74), (5) octahydrobenzo(f)quinolines (44), (6) octahydrobenzo(g)quino l i n e s (46, 75), (7) phenanthrenes (76), (8) i m i d a z o l i n e s (77), (9) p i p e r a z i n e s (78), and (10) e r g o l i n e s (79-83). The t e t r a h y dro-3-benzazepines (5-10), such as I - I I I , represent a r e l a t i v e l y recent a d d i t i o n to the l i s t . The s t r u c t u r a l f e a t u r e s required f o r binding at b r a i n DA receptor (D , [^H]-neuroleptic l a b e l l e d ) s i t e s have been summarized (58). These are: (1) a hydrogen bonding group at a p o s i t i o n equivalent to the meta-OH of DA and p o s s i b l y an accessory hydrogen bonding s i t e at a p o s i t i o n complementary to the para-OH, (2) n o n - e s s e n t i a l , but potency enhancing, f a t s o l u b i l i t y , (3) a basic Ν l o c a t e d about 0.6 A from the plane of the r i n g bearing the hydrogen bonding groups, (4) a d i s t a n c e of l e s s than 7.3 A between the OH (or OH-simulating) group and the b a s i c Ν (a minimum distance i s not e s t a b l i s h e d , but i t i s i n t e r e s t i n g to note that 4-hydroxy-2-dipropylaminoindan (73) which has an Ν t o 0 d i s t a n c e of 5.5 A i s more potent than i t s 5-CH isomer that has a g r e a t e r Ν to 0 d i s t a n c e ) , and (5) s t e r i c hindrance f a c t o r s or s i t e s of bulk i n t o l e r a n c e , one of which i s l o c a t e d near the Ν binding s i t e that would hinder accommodation of a t i l t e d r i n g as i n octahydrobenzo(g)quinolines and groups l a r g e r than p r o p y l i n N-substituted norapomorphine (46) and another, equivalent to the s i t e of s t e r i c hindrance i n the model depicted i n F i g u r e 2, that i n t e r f e r e s with attachment of octahydrobenzo(h)quinolines (84), isoapomorphine (85) and a p p r o p r i a t e l y s u b s t i t u t e d dihydrophenanthrenes (76). Even these d e t a i l e d s t r u c t u r a l requirements are met i n some compounds, namely, p r o p e r l y s u b s t i t u t e d p i p e r i d i n e s (61, 86), e.g., 2-(3,4-dihydroxybenzyl)piperidine, and r e l a t e d 2



234

DOPAMINE

Figure 2,

RECEPTORS

Hypothetical binding of (R)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene to postulated DA receptor (11).



10.

KAISER

Stereoisomeric

Probes

235

l - ( 3 , 4 - d i h y d r o x y b e n z y l ) t e t r a h y d r o i s o q u i n o l i n e s (61), that l a c k s i g n i f i c a n t DA-like a c t i v i t y . One of these, N-(n-propyl)-3-(3hydroxyphenyl)piperidine (3-PPP) i s a potent agonist of DA auto receptors (86) suggesting that some DA receptor subtypes may have d i f f e r e n t s t r u c t u r a l requirements. The g e n e r a l SAR requirements summarized f o r DA r e c e p t o r a g o n i s t s (58), as w e l l as c o n s i d e r a t i o n of the s t e r i c r e q u i r e ments of dopaminergic drugs (87), have l e d to suggestions of v a r i o u s models to r a t i o n a l i z e the i n t e r a c t i o n of these agents with the receptor. Many of these models (e.g., 88-91) suggest modes of receptor binding and s t e r i c parameters. They g e n e r a l l y suggest a s t e r i c s i t e on the receptor that r e s i s t s bulk on the p a r t of the DA agonist molecule on the s i d e opposite the OH that i s "meta" to the ethylamine s i d e c h a i n . These s t u d i e s , however, are of l i t t l e a p p l i c a t i o n i n r a t i o n a l i z i n g e n a n t i o s e l e c t i v i t y . Apomorphine i s e n a n t i o s e l e c t i v e ; the " n a t u r a l " (-)-enantiomer, having the absolute 6alt stereochemistry, has dopaminergic a c t i v i t y (15). T h i s e n a n t i o s e l e c t i v i t y of DA receptors was l a t e r confirmed by r e s o l u t i o n , determination of absolute stereochemis t r y and study of a number of hydroxy1-substituted 2-amino-l,23,4-tetrahydronapthalene d e r i v a t i v e s (18, 48, 94). Information obtained from these s t u d i e s was employed by McDermed (17) f o r d e r i v a t i o n of an a p p e a l i n g l y simple schematic model c o n s i s t e n t with observed e n a n t i o s e l e c t i v i t y . T h i s model suggests r e c e p t o r i n t e r a c t i o n w i t h the OH group "meta" to the ethylamine s i d e c h a i n i n the DA framework, a p r o p e r l y o r i e n t e d b a s i c amine and a r e g i o n of bulk i n t o l e r a n c e as i l l u s t r a t e d i n F i g u r e 2 f o r (R)-2-amino-6, 7-dihydroxy-l,2,3,4-tetrahydronaphthalene (ADTN). The s i t e of s t e r i c hindrance, i n d i c a t e d by the l i n e d area i n F i g u r e 2 (17) was supported by examination of 5- and 8-propyl d e r i v a t i v e s ; as expected the 8-, but not the 5-isomer, was a f a i r l y potent DA receptor agonist (19). The benzazepines I - I I I are not r e a d i l y incorporated i n t o t h i s model f o r s e v e r a l reasons. F i r s t l y , both of the c a t e c h o l i c OHs i n I - I I I are "meta" to an ethylamine c h a i n and both are es s e n t i a l f o r a c t i v i t y (5, 35). In a d d i t i o n , e i t h e r the 6-C1 or the 1-phenyl s u b s t i t u e n t must r e s i d e near the p o s t u l a t e d s i t e of bulk i n t o l e r a n c e (51). As i l l u s t r a t e d i n F i g u r e s 3 and 4 (36), at l e a s t two p l a u s i b l e i n t e r p r e t a t i o n s of the e n a n t i o s e l e c t i v i t y of I - I I I may be advanced to accommodate t h i s model. In these F i g u r e s , the p o s s i b i l i t y i s a l s o advanced that receptor i n t e r a c t i o n might conceivably i n v o l v e the ρ o r b i t a l s of an OH group. As i n d i c a t e d i n F i g u r e 3, the phenyl or s u b s t i t u t e d phenyl group of ( R ) - I - I I I might be accommodated as a r e s u l t of i t s being i n an α-orientation that avoids the s i t e of s t e r i c hindrance. An a l t e r n a t i v e p o s s i b i l i t y , suggested i n F i g u r e 4, i s that i n t e r a c t i o n might i n v o l v e the N, the N - a l l y l (except i n the case of ( S ) I I I , i n which case t h i s group may meet a secondary s i t e of bulk i n t o l e r a n c e , suggested by Seeman (58) as being near the N-binding s i t e ) , the 6-chloro, the c a t e c h o l i c OHs, and the phenyl or 4'-


DOPAMINE

RECEPTORS


236

Figure 4. Alternative possible mode of binding of (R)-I-III to postulated DA receptor. (Reproduced with permission from Ref. 36. Copyright, Swedish Academy of Pharmaceutical Science.)


10.

KAISER

Stereoisomeric

Probes

hydroxyphenyl, a l l of which, as noted p r e v i o u s l y , increase some kinds of DA-like a c t i v i t y . A preference f o r t h i s l a t t e r i n t e r p r e t a t i o n i s suggested by s e v e r a l other DA receptor models, a l luded to i n the subsequent d i s c u s s i o n , that p o s t u l a t e an acces sory binding s i t e f o r the phenyl group i n t h i s g e n e r a l l o c a t i o n . P o s s i b l y as a r e s u l t of the requirement of both OHs, the mode of i n t e r a c t i o n of the benzazepines with DA receptors i s somewhat a l t e r e d so that C l s u b s t i t u e n t can f i t the receptor and even provide enhanced binding, perhaps by i n c r e a s i n g the a c i d i t y of the adjacent OH (39) >

Stereoisomeric Probes of the Dopamine Receptor - American

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