Conformationally Defined Pyrroloisoquinoline Antipsychotics

groups are defined by dopamine, dopamine agonists such as (R>- .... 0 lf de g. 9. 2,de g τ. , de g. (R)-a porn o. r p h i η e. -. 1. 5.1. 2. 99. 1. ...
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Implications for the Mode of Interaction of Antipsychotic Drugs with the Dopamine Receptor G . L . O L S O N , H . - C . C H E U N G , E . C H I A N G , and L . B E R G E R Hoffmann-La Roche Inc., Chemical Research Department, Nutley, NJ 07110

The p y r r o l o - and c y c l o a l k a [4,5] p y r r o l o [2,3-g] i s o q u i n o l i n e ring s y s t e m s (1) w e r e designed on the basis of a h y p o t h e t i c a l m o d e l of the i n t e r a c t i o n of a n t i p s y c h o t i c drugs w i t h the dopamine r e c e p t o r . The p r o t o t y p e ( 1 a ) ( 2 , 6 - d i m e t h y l - 3 - e t h y l 4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g] isoquinolin-4-one) ( R o 22-1319) i s a p o t e n t , s e l e c t i v e D-2 dopamine receptor antagonist which exhibits potent a n t i p s y c h o t i c - l i k e a c t i v i t y i n a n i m a l tests and is b e i n g evaluated clinically. A series of analogs has been s y n t h e s i z e d to probe the e f f e c t s of substituents and r i n g s i z e on p h a r m a c o l o g i c a l activity a n d r e c e p t o r b i n d i n g . I n t r o d u c i n g bulky groups i n the 2- and 3-positions, o r i n c r e a s i n g r i n g s i z e in the c y c l o a l k a analogs d i m i n i s h e s activity a n d r e v e a l s a s t e r i c b a r r i e r near the 2 - p o s i t i o n . A wide range of substituents on the b a s i c n i t r o g e n are c o n s i s t e n t w i t h pharmacological a c t i v i t y , but only compounds having l i p o p h i l i c substituents are p r o p o r t i o n a l l y potent i n H- s p i r o p e r i d o l b i n d i n g . The r e s u l t s suggest that i n t e r a c t i o n s of the n i t r o g e n substituent w i t h the a u x i l i a r y b i n d i n g s i t e i d e n t i f i e d i n the m o d e l modulates the activity b e t w e e n D - 1 and D-2 d o p a m i n e r e c e p t o r s . 3

A n t i p s y c h o t i c drugs have e m e r g e d f r o m a w i d e v a r i e t y of s t r u c t u r a l classes ( F i g u r e 1) i n c l u d i n g t r i c y c l i c s such as the p h e n o t h i a z i n e s and thioxanthenes, butyrophenones, d i p h e n y l b u t y l p i p e r i dines, benzamides, indolones and o t h e r s . D e s p i t e t h i s s t r u c t u r a l d i v e r s i t y , a l l of these drugs have the c o m m o n p r o p e r t y of a c t i n g as p o s t s y n a p t i c d o p a m i n e r e c e p t o r a n t a g o n i s t s , a l t h o u g h t h e i r r e l a t i v e a f f i n i t y f o r d i f f e r e n t subpopulations of receptors may differ. Structural Requirements O v e r the years t h e r e has been an e v o l u t i o n i n understanding the structural requirements for dopamine antagonist a c t i v i t y and i n 0097-6156/83/0224-0251$07.00/0 © 1983 American Chemical Society In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

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a p p r e c i a t i n g the c o m m o n c h a r a c t e r i s t i c s of these d i v e r s e s t r u c t u r e s . F o r e x a m p l e , Janssen (1) d e v e l o p e d a l i n e a r c l a s s i f i c a t i o n s c h e m e ( F i g u r e 2) w h i c h i n d i c a t e d the presence of an a r o m a t i c m o i e t y s e p a r a t e d by a short c h a i n (usually of four atoms) f r o m a b a s i c n i t r o g e n i n these compounds. A composite picture ( F i g u r e 3) c o n t a i n i n g f e a t u r e s of many k n o w n a n t i p s y c h o t i c s was d e v i s e d by G s c h w e n d (2), a n d conveys m o r e s t r u c t u r a l information. The advent of dopamine r e c e p t o r b i n d i n g assays (3) i s a k e y d e v e l o p m e n t t h a t continues to i n f l u e n c e the s t u d y 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 a m o n g a n t i p s y c h o t i c s . A major insight f r o m b i n d i n g assays is the r e c o g n i t i o n t h a t the c o m m o n p r o p e r t y of d i v e r s e s t r u c t u r a l types of b o t h agonist and a n t a g o n i s t drugs is t h e i r i n t e r a c t i o n w i t h c l o s e l y r e l a t e d m a c r o m o l e c u l a r r e c e p t o r s . F e i n b e r g a n d S n y d e r (4) r e c o g n i z e d the t h r e e d i m e n s i o n a l s t r u c t u r a l r e l a t i o n s h i p b e t w e e n l o w energy c o n f o r m e r s of dopamine and antagonists of the tricyclic phenothiazene class (e.g. c h l o r p r o m a z i n e , F i g u r e 4). H u m b e r (5) b u i l t f e a t u r e s of the t r i c y c l i c antagonists and f e a t u r e s of the agonist apomorphine i n t o the r e l a t i v e l y r i g i d and c h i r a l f r a m e w o r k of b u t a c l a m o l ( F i g u r e 5). These studies p r o v i d e d the f i r s t t h r e e - d i m e n s i o n a l r e p r e s e n t a t i o n s of the p h a r m a c o p h o r e . H u m b e r s s t r u c t u r e - a c t i v i t y studies (g, I) o n b u t a c l a m o l and analogs p r o v i d e d a u s e f u l a b s t r a c t r e p r e s e n t a t i o n ( F i g u r e 6) o f the shape and g e o m e t r y of a r e c e p t o r s u r f a c e . !

A Hypothetical Receptor Model Our a p p r o a c h t o understand how the d i f f e r e n t classes of a n t i p s y c h o t i c drugs are r e l a t e d has been t o use what is k n o w n about the s t r u c t u r e s and p h a r m a c o p h o r i c groups of the drug compounds t o i n f e r a h y p o t h e t i c a l m o l e c u l a r s t r u c t u r e of the r e c e p t o r b i n d i n g s i t e . B y t h i s a p p r o a c h , w e are a t t e m p t i n g t o t r e a t the b i n d i n g of drugs t o r e c e p t o r s i n analogy t o s m a l l molecule-protein interactions, such as those observed in X-ray c r y s t a l l o g r a p h i c studies of e n z y m e - s u b s t r a t e / i n h i b i t o r c o m p l e x e s . The d o p a m i n e r e c e p t o r m o d e l (8) has been d e v e l o p e d by c o n s i d e r i n g p l a u s i b l e i n t e r m o l e c u l a r i n t e r a c t i o n s b e t w e e n f u n c t i o n a l groups on the drug compounds and c o m p l e m e n t a r y a m i n o a c i d side c h a i n f u n c t i o n a l groups that m i g h t be present on a d o p a m i n e r e c e p t o r p r o t e i n . F r o m this basis, the t h r e e d i m e n s i o n a l r e l a t i o n s h i p of these h y p o t h e t i c a l r e c e p t o r groups has been mapped using i n f o r m a t i o n f r o m compounds of d i f f e r e n t s t r u c t u r a l classes and r i g i d analogs (8). In t h i s a r t i c l e the basis of the h y p o t h e t i c a l m o d e l is r e v i e w e d b r i e f l y a n d 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 f r o m a series of compounds designed and m o d i f i e d on the basis of the m o d e l are presented. In a g r e e m e n t w i t h previous w o r k , the e s s e n t i a l pharm a c o p h o r i c groups are d e f i n e d by d o p a m i n e , d o p a m i n e agonists s u c h as (R>a p o m o r p h i n e , a n d n e u r o l e p t i c drugs, w h i c h a l l possess a b a s i c n i t r o g e n a t o m s e p a r a t e d by a 5-7 Â c h a i n or f r a m e w o r k f r o m an a r o m a t i c r i n g . It appears reasonable t o assume t h a t t h e s e t w o groups are p h a r m a c o p h o r e s f o r agonists and antagonists and a r e bound t o c o m p l e m e n t a r y f u n c t i o n a l i t y on the r e c e p t o r p r o t e i n ( F i g u r e 7). W e i m a g i n e the b a s i c a m i n o group of the drug t o bind t o an a c i d i c a m i n o a c i d residue (e.g., A s p , G l u ; perhaps the

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

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E TA L .

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Antipsychotics

HALOPERIDOL

PIMOZIDE

( BUTYROPHENONE)

( Dl PH EN YLBUTYLPI PERI DINE)

0 CH CH 2

3

CX ' UQK

3

S0 NH 2

2

SULPIRIDE

MOLINDONE

( BENZAMIOE)

(INDOLONE)

Figure 1.

Figure 2.

Representative antipsychotic drugs.

I.

A-C-C-C-C- Ν-C

2.

A - C = C - C - C - Ν-- C

3.

A-N-C-C-C- Ν -C

4.

A-O-C-C-C- Ν -C

5.

A-S-C-C-C- Ν-C

6.

A - C - N - C - C - •Ν - C

7.

A-C-O-C-C- Ν-C

8.

A A ' - C - C - N - -C

9.

A'-C-C-N-C

Classification scheme for neuroleptics. (Reproduced with permission from Réf. 1. Copyright 1973, Pergamon Press Ltd.)

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

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Figure 3. Composite structure for neuroleptics. (Reproduced with permission from Ref. 2. Copyright 1974, Futura Publishing Company, Inc.)

Figure 4. Relationship between chlorpromazine and dopamine. (Reproduced with permission from Ref. 4.)

Figure 5. Relationship between (R)apomorphine and (+)-butaclamol/(-{-)dexclamol (5).

(+)-

BUTACLAMOL

(R=C(CH ) )

(+)-

DEXCLAMOL

(R=CH(CH ) )

3

(R)-APOMORPHINE

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

3

3

2

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Figure 6.

Pyrroloisoquinoline

Antipsychotics

Receptor binding site model proposed by Humber (6,1).

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

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256

DOPAMINE

Ο

AMMONIUM- CARBOXYLATE RECEPTOR

•COO

RECEPTORS

H

H - N H DRUG

II

I — 2.9A-A

I R

ACIDIC AMINO ACID GROUPS π

- π

"STACKING"

R = CH COOH 2

Asp

CH CH COOH 2

C H

2

2

Glu

— ^ ^ - O H

Tyr

AROMATIC AMINO ACID GROUPS η - ΤΤ

R =

INTERACTION

DRUG

C H

C H

Ι29Ρ Ό

2

2

— P h e

— ^ ^ - O H

Tyr

ι

~Τ7 3.6Α

C

H

2

RECEPTOR

" t n ©

T r y

CH.

Figure 7.

Drug-receptor interactions invoked in hypothetical dopamine receptor model.

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

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Antipsychotics

257

p h e n o l i c O H of T y r ) . W e consider the a r o m a t i c r i n g t o f o r m a ττ- π s t a c k i n g i n t e r a c t i o n w i t h an a r o m a t i c a m i n o a c i d residue (e.g., P h e , T y r , T r y , H i s ) . A l s o i n v o k e d i n our m o d e l is the i n t e r a c t i o n of the nonbonded l o n e p a i r e l e c t r o n s of a c a r b o n y l oxygen w i t h an a r o m a t i c a m i n o a c i d residue (see b e l o w ) . The p l a u s i b i l i t y of these i n t e r a c t i o n s has been p r e v i o u s l y discussed (8). The s e p a r a t i o n b e t w e e n the r e c e p t o r f e a t u r e s w h i c h b i n d the a r o m a t i c r i n g a n d the b a s i c n i t r o g e n and the g e o m e t r i c a l r e l a t i o n s h i p b e t w e e n them can be d e f i n e d by c o n s i d e r i n g how r e p r e s e n t a t i v e compounds ( e s p e c i a l l y r i g i d analogs) c o u l d b i n d . W e have used a s i m p l e g e n e r a l s c h e m e ( F i g u r e 8) t o describe the r e l a t i o n s h i p b e t w e e n the a r o m a t i c and basic a m i n e p h a r m a c o p h o r i c groups i n d e p e n d e n t l y of the c o n n e c t i n g a t o m s . The d a t a for the t o r s i o n angle τ shows the B c o n f o r m e r of (+)-dexclamol to r e s e m b l e apomorphine m o r e c l o s e l y t h a n the A c o n f o r m e r f o u n d i n the c r y s t a l of (+)-butaclamol, i n a g r e e m e n t w i t h Humberts m o d e l (5, 6, 7). When t h i s m o d e l of i n t e r a c t i o n is a p p l i e d t o other classes of a n t i p s y c h o t i c compounds ( F i g u r e 9) t w o other f e a t u r e s of the b i n d i n g s i t e emerge. Thus, i n d e x c l a m o l , a l l t r i c y c l i c , a n d d i p h e n y l b u t y l p i p e r i d i n e c o m p o u n d s , a s e c o n d a r o m a t i c r i n g appears at a l o c a t i o n w h i c h c o u l d m a t c h t h a t o c c u p i e d by r i n g C of d e x c l a m o l . In butyrophenones, the presence of a k e t o n e c a r b o n y l i n s t e a d of this s e c o n d a r o m a t i c m o i e t y i s a p p a r e n t . A c a r b o n y l group at t h i s p o s i t i o n i s also seen i n a t y p i c a l n e u r o l e p t i c s s u c h as m o l i n d o n e and the b e n z a m i d e s . S i n c e the c o m m o n c h a r a c t e r i s t i c of a c a r b o n y l oxygen and an a r o m a t i c r i n g i s t h e i r l o c a l i z a t i o n of e l e c t r o n d e n s i t y , w e s p e c u l a t e t h a t a t h i r d m o l e c u l a r f e a t u r e on the r e c e p t o r m a y be another a r o m a t i c a m i n o a c i d r e s i d u e . T h i s residue c o u l d b i n d r i n g C of d e x c l a m o l or the s e c o n d a r o m a t i c r i n g of the t r i c y c l i c s or d i p h e n y l b u t y l p i p e r i d i n e s by a s t a c k i n g i n t e r a c t i o n . The c a r b o n y l groups of the o t h e r n e u r o l e p t i c s c o u l d bind by i n t e r a c t i o n of the η e l e c t r o n s w i t h the f a c e of the a r o m a t i c r i n g of the r e c e p t o r . T o our k n o w l e d g e , a l l dopamine r e c e p t o r antagonist drugs possess f u n c t i o n a l i t y c a p a b l e of d o n a t i n g electrons in this manner. T h i s t h i r d b i n d i n g s i t e w o u l d not be o c c u p i e d by f u n c t i o n a l i t y on d o p a m i n e or r i g i d congeners s u c h as A D T N , a n d the s e c o n d a r o m a t i c r i n g o f ( R ) - a p o m o r p h i n e i s d i r e c t e d a w a y f r o m this s i t e . These o b s e r v a t i o n s o f f e r a t e n t a t i v e m o l e c u l a r r a t i o n a l i z a t i o n of the m e c h a n i s m of antagonism by i m p l y i n g t h a t b i n d i n g t h i s t h i r d s i t e by s o m e e l e c t r o n e g a t i v e group leads t o a n t a g o n i s t a c t i v i t y a n d i s unnecessary f o r agonist a c t i v i t y . A f o u r t h b i n d i n g r e g i o n of l o w s t r u c t u r a l s p e c i f i c i t y c a n also be i d e n t i f i e d (dashed box i n F i g u r e 9). It m a y b i n d bulky a l k y l or a r y l groups and a v a r i e t y of s p i r o p i p e r i d i n e or b e n z i m i d a z o l o n e groups seen i n the butyrophenone analogs. T h i s s i t e i s most p r o b a b l y a l i p o p h i l i c c a v i t y of l a r g e d i m e n s i o n n e a r e s t the b i n d i n g s i t e f o r the b a s i c n i t r o g e n . S i n c e s e v e r a l p h a r m a c o l o g i c a l l y a c t i v e compounds l a c k l i p o p h i l i c f u n c t i o n a l i t y t o o c c u p y t h i s s i t e , i t i s r e f e r r e d t o as an a u x i l i a r y b i n d i n g s i t e . S t r u c t u r e a c t i v i t y a n d r e c e p t o r b i n d i n g studies (see below) suggest that the a u x i l i a r y b i n d i n g s i t e d i s c r i m i n a t e s D - 1 a n d D - 2 d o p a m i n e r e c e p t o r antagonists (9). D e v e l o p m e n t of a P y r r o l o i s o q u i n o l i n e A n t i p s y c h o t i c ( R o 22-1319) S t u d y of this r e c e p t o r m o d e l l e d t o the design of a series of 4 a , 8 a t r a n s - p y r r o l o [2,3-g] i s o q u i n o l i n e derivatives (e.g., R o 22-1319, l a )

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

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

5.13

5.93

(+)-butaclamol ( c o n f o r m e r A)

pyrroloisoquinoline (-)-la

deg

99.1

l f

88.6

84.3

101.3

104.1

0

90.6

95.5

108.6

101.9

99.4

2

9 ,deg

-19.1

65.1

45.3

7.7

-9.1

τ, deg

Angular relationships of pharmacophores in drugs acting at dopamine receptors ($).

4.92

(+)-dexclamol ( c o n f o r m e r Β)

Figure 8.

5.09

(Β)-apomorphine-2

A

5.12

Ul'

(R)-a porno r ph i η e -1

Compound

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Pyrwloisoquinoline

PIMOZIDE

259

Antipsychotics

^ ~- PYRROLOISOQUINOLINE la

Figure 9. Receptor interactions of diverse antipsychotic drugs. Key: ir aromatic groups; COO~, carboxylate groups; and , auxiliary binding site ($). u

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

DOPAMINE

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260

RECEPTORS

i n c o r p o r a t i n g s o m e f u n c t i o n a l i t y c o n c e p t u a l l y d e r i v e d f r o m molindone and a c o n f o r m a t i o n and c o n f i g u r a t i o n b u i l t i n t o a r i g i d m o l e c u l a r f r a m e w o r k t o c o n f o r m to the r e c e p t o r m o d e l . The 4a,8a-trans r i n g fusion of these compounds assures that the a r o m a t i c r i n g , n i t r o g e n l o n e p a i r , a n d c a r b o n y l group are f i x e d i n an o r i e n t a t i o n t o o p t i m i z e r e c e p t o r i n t e r a c t i o n w i t h the f i r s t , s e c o n d , a n d t h i r d e s s e n t i a l b i n d i n g s i t e s , r e s p e c t i v e l y . The t o r s i o n angle τ ( F i g u r e 8) b e t w e e n the n o r m a l to the a r o m a t i c r i n g a n d the n i t r o g e n - n i t r o g e n l o n e p a i r bond i n these compounds is -19 . T h u s , i n t e r m s of c o n f o r m a t i o n , l a resembles apomorghine (τ =-9.1 ) m o r e c l o s e l y than d e x c l a m o l (conformer Β) ( τ = 45.3 ). N e v e r t h e l e s s , the e x t r e m e s i n the t o r s i o n angle τ ( - 1 9 ° t o + 4 5 . 3 ° ) i n the antagonist compounds represents only a n a r r o w range ( ± 3 2 . 5 ° c e n t e r e d about 1 2 . 5 ° ) t h a t is e a s i l y a c c o m m o d a t e d by s m a l l motions of the r e c e p t o r (vide i n f r a ) . We have m o d e l e d the k e y i n t e r a c t i o n s d e s c r i b e d w i t h d e x c l a m o l (conformer B) a n d our p y r r o l o i s o q u i n o l i n e using O R T E P a n d w i t h s p a c e ­ f i l l i n g models ( F i g u r e 10). The r e l a t i o n s h i p b e t w e e n the p h a r m a c o p h o r i c groups i n t w o d i f f e r e n t s t r u c t u r e s is usually t r e a t e d by p e r f o r m i n g a l e a s t squares s u p e r p o s i t i o n of a t o m s thought to be p a r t of the p h a r m a c o p h o r e . A s i l l u s t r a t e d i n F i g u r e 10, t h i s a p p r o a c h has been m o d i f i e d t o i n c l u d e the k e y m o l e c u l a r features of the r e c e p t o r s i t e i n the f i t t i n g as they a r e o r i e n t e d t o b i n d b o t h d e x c l a m o l ( c o n f o r m e r Β) a n d l a . When the r e c e p t o r groups are v i e w e d i n t h i s s u p e r p o s i t i o n i n the absence of the drug m o l e c u l e s , the v a r i a t i o n i n the p o s i t i o n of the r e c e p t o r groups m a y be c o n s i d e r e d t o represent the e x t e n t of m o t i o n r e q u i r e d by the r e c e p t o r t o bind b o t h drugs o p t i m a l l y . A s is evident f r o m the f i g u r e , s u c h m o t i o n s represent only s l i g h t changes i n the p o s i t i o n and o r i e n t a t i o n of a m i n o a c i d side c h a i n groups. N o gross a l t e r a t i o n i n the s e c o n d a r y s t r u c t u r e of the r e c e p t o r p r o t e i n needs to be i n v o k e d t o understand the a d a p t a t i o n of the r e c e p t o r t o these d i f f e r e n t drug l i g a n d s . P h a r m a c o l o g y a n d B i o c h e m i s t r y of R o 22-1319 The p y r r o l o i s o q u i n o l i n e d e r i v a t i v e R o 22-1319 ( l a ) has been s h o w n t o e x h i b i t potent a n t i p s y c h o t i c - l i k e a c t i v i t y i n p h a r m a c o l o g i c a l tests (10) (Table I). In the a v o i d a n c e t e s t , R o 22-1319 i s i n the p o t e n c y range of h a l o p e r i d o l and over f i v e t i m e s the p o t e n c y of m o l i n d o n e . The b i o l o g i c a l a c t i v i t y i s h i g h l y s t e r e o s e l e c t i v e , w i t h v i r t u a l l y a l l the a c t i v i t y r e s i d i n g i n the 4 a R , 8 a R - e n a n t i o m e r ( - ) - l a . In other aspects of its p h a r m a c o l o g y , R o 22-1319 r e s e m b l e s h a l o p e r i d o l , e x c e p t t h a t i t has r e l a t i v e l y w e a k e r c a t a l e p t o g e n i c and a n t i s t e r e o t y p i c a c t i v i t y a n d w e a k e r a u t o n o m i c e f f e c t s . It has m i n i m a l a c t i v i t y i n a r a t c h r o n i c s t e r e o t y p y m o d e l of r e c e p t o r s u p e r s e n s i t i v i t y , i n d i c a t i n g a l o w p o t e n t i a l for t a r d i v e d y s k i n e s i a . R e c e n t b i o c h e m i c a l studies (11) i n d i c a t e t h a t R o 22-1319 has sodium-dependent b i n d i n g p r o p e r t i e s and has no e f f e c t on the d o p a m i n e - s t i m u l a t e d a d e n y l a t e c y c l a s e D - 1 r e c e p t o r w h i c h c h a r a c t e r i z e i t as a s p e c i f i c D - 2 d o p a m i n e r e c e p t o r antagonist l i k e s u l p i r i d e , m e t o c l o p r a m i d e , a n d m o l i n d o n e (9. 12). E a r l y c l i n i c a l t r i a l s support the conclusions f r o m a n i m a l models t h a t R o 2 2 1319 i s an e f f i c a c i o u s a n t i p s y c h o t i c agent w i t h m i n i m a l e x t r a p y r a m i d a l effects.

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

OLSON

ET AL.

Pyrwloisoquinoline

Antipsychotics

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11.

261

en

ft. S

I

n

1

c

.3

S

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

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

Figure 1 Ob. Pyrroloisoquinoline (-)-la

and idealized receptor groups.

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I

H

8

w

w

3

> g

S

to to Os

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

Figure 10c.

Least-squares superposition of Figure 10a and Figure 10b which shows the motion of receptor groups required to bind both compounds optimally.

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264

DOPAMINE

RECEPTORS

0

Ιο ( R022-I3I9)

Activity

Table I o f Compounds i n t h e Rat D i s c r e t e A v o i d a n c e Avoidance Blockade ABD50 mg/kg p . o .

Compound

(-)-la'HCl

0.72 ( 0 . 4 3 - 1 . 2 6 )

(-)-la-HCl

0.49

(+)-la-HCl

(0.17-0.66)

molindone

3.6

(0.5-10.5)

Figures

9.8

3

3.6 b

6.0 0.35

Not

Escape Blockade EBD20 mg/kg p . o .

(0.18-1.22)

haloperidol

i n p a r e n t h e s e s a r e 95% c o n f i d e n c e

applicable

because

Test

2.7 17.1

limits.

of lack of avoidance

blockade.

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

11.

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ET AL.

Pyrroloisoquinoline

Antipsychotics

265

Synthesis and 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

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The h y p o t h e t i c a l m o d e l used i n the design of R o 22-1319 has p r o v e d t o be of c o n s i d e r a b l e value i n designing analogs and i n i n t e r p r e t i n g 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 . W e have been p a r t i c u l a r l y i n t e r e s t e d i n p r e p a r i n g s p e c i f i c compounds to f a v o r or d i s f a v o r c e r t a i n i n t e r a c t i o n s w i t h the e s s e n t i a l b i n d i n g sites and t o e x p l o r e the c h a r a c t e r i s t i c s of the auxiliary binding site. The compounds w e r e s y n t h e s i z e d (Scheme I) v i a a K n o r r c o n d e n s a t i o n of a 2 - i s o n i t r o s o k e t o n e (ii) and Z n or an a m i n o k e t o n e (iii) w i t h the N m e t h y l o c t a h y d r o i s o q u i n o l i n e d i o n e (i) . A n e w , i m p r o v e d r o u t e t o the d i k e t o n e (i) d e v e l o p e d by D r s . D . C o f f e n and U . H e n g a r t n e r has c o n t r i b u t e d s i g n i f i c a n t l y t o the p r o j e c t . D e m e t h y l a t i o n of the i n i t i a l product (iv) using e t h y l c h l o r o f o r m a t e f o l l o w e d by a l k a l i n e h y d r o l y s i s gave the s e c o n d a r y a m i n e (v) w h i c h was a l k y l a t e d w i t h a v a r i e t y of a l k y l a t i n g agents to give a range of analogs (1). The major products from b o t h the K n o r r condensation and the a l k y l a t i o n steps were 4a,8a-trans i s o m e r s ; these w e r e e a s i l y s e p a r a t e d f r o m the m i n o r 4 a , 8 a - c i s compounds by c h r o m a t o g r a p h y or c r y s t a l l i z a t i o n . P y r r o l o i s o q u i n o l i n e analogs h a v i n g s u b s t i t u e n t s i n the 2 - and 3 positions (Table II) r a n g i n g i n s i z e f r o m H to i s o p r o p y l and phenyl w e r e p r e p a r e d . The u n s u b s t i t u t e d c o m p o u n d (2) was r e l a t i v e l y w e a k w i t h d i a l k y l s u b s t i t u t i o n by s t e r i c a l l y n o n - d e m a n d i n g groups (4, l a , 5) g i v i n g the m o s t potency. Isopropyl s u b s t i t u t i o n i n the 3 - p o s i t i o n (6) decreases a c t i v i t y s o m e w h a t r e l a t i v e t o the n - p r o p y l group (5) , w h i l e i s o p r o p y l i n the 2 p o s i t i o n (7) decreases a c t i v i t y m o r e , as does a p h e n y l group i n the 3 p o s i t i o n (8). The p h e n y l group c e r t a i n l y w o u l d i n t e r f e r e w i t h a s t a c k i n g i n t e r a c t i o n . The g r e a t e r s e n s i t i v i t y of the 2 - p o s i t i o n t o bulky groups m a y r e f l e c t b o t h an e f f e c t on s t a c k i n g and the possible presence of a s t e r i c c o n t a c t or b a r r i e r near t h a t g r o u p . The i m p o r t a n c e of this b a r r i e r c a n also be seen i n the c y c l i c a n a l o g s . A s r i n g s i z e was i n c r e a s e d i n the c y c l o a l k a [ 4,5] p y r r o l o i s o q u i n o l i n e s (Table III), t h e r e was a s t e a d y d e c r e a s e i n p o t e n c y f r o m the 5- to 6- t o 7m e m b e r e d a n a l o g s ( 9 , 1 0 , 1 1 ) . The s u b s t i t u e n t m e t h y l e n e s adjacent t o the p y r r o l e r i n g w o u l d be e x p e c t e d t o l i e r o u g h l y i n the plane of the p y r r o l e r i n g i n t h e s e analogs, so the d e c r e a s e d p o t e n c y s e e m s less l i k e l y t o be due t o i n t e r f e r e n c e w i t h s t a c k i n g t h a n t o s t e r i c i n t e r f e r e n c e of the m e t h y l e n e s f u r t h e r f r o m the p y r r o l e w i t h the b a r r i e r m e n t i o n e d p r e v i o u s l y near the 2 p o s i t i o n . The r e t u r n of a c t i v i t y i n the 8 - m e m b e r e d a n a l o g (12) c a n be a t t r i b u t e d t o p u c k e r i n g of the r i n g t o a v o i d the i n t e r a c t i o n w i t h the barrier. The A u x i l i a r y B i n d i n g S i t e and S e l e c t i v i t y f o r D - 2 a n d D - 1 D o p a m i n e Receptor's A l a r g e number of analogs b e a r i n g l i p o p h i l i c s u b s t i t u e n t s on the b a s i c n i t r o g e n have been p r e p a r e d (Table IV) t o probe the c h a r a c t e r i s t i c s of the a u x i l i a r y b i n d i n g s i t e . A s i s evident f r o m the t a b l e , a l l of the analogs

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

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266 DOPAMINE RECEPTORS

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

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11.

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ET AL.

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Antipsychotics

Table I I . E f f e c t of s u b s t i t u e n t bulk at 2- and 3 - p o s i t i o n s on activity.

CH N 3

l

1

J 2

H

COMPOUND

AVOIDANCE ABD50 mg/kg po

R„

4.12

H

2 3

CH,

H

1.98

4

CH,

CH,

0.47

la

CH,

CH CH

5

CH,

CHgCH 2 CH

6

CH,

CH(CH )

7

CH(CH )

8

CH,

2

0.7

3

3

3

2

CH

3

2

3

0.46 1.22 35 8po = IO%

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

268

DOPAMINE

RECEPTORS

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Table I I I . E f f e c t of r i n g s i z e i n cycloalka(4,5)pyrrolo(2,3-g)i s o q u i n o l i n e s on a c t i v i t y .

COMPOUND

RING

AVOIDANCE ABD50 mg/kg po

0.98

10

/to OO

12

40

5.50

50% AB at 16 po

7.3

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

11.

OLSON

Pyrwloisoquinoline

ET A L .

Table IV.

E f f e c t of l i p o p h i l i c groups at b a s i c n i t r o g e n on a c t i v i t y .

H

3

H

AVOIDANCE

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269

Antipsychotics

ABD50 COMPOUND

R

m g / k g po

4

3

H - SPIROPERIDOL BINDING

IC50

ηM

13

H

Ια

CH

14

CH CH

15

CH CH = C H

16

CH CH CH

17

CH — 1000 u M ) , whereas the N - b e n z y l a n a l o g 17 is a potent D - 1 a n t a g o n i s t (IC = 0.43^). R e c e n t l y , N a k a m u r a and K u r u m a (11) have d e m o n s t r a t e d t h a t H R o 22-1319 b i n d i n g i s c r i t i c a l l y dependent on the presence of sodium i o m i n t h i s respect r e s e m b l i n g Η - s u l p i r i d e b i n d i n g , a n d c o n t r a s t i n g w i t h Hs p i r o p e r i d o l b i n d i n g , w h i c h i s sodium i n d e p e n d e n t . In a d d i t i o n , J i k e D - 2 a n t a g o n i s t i c a n t i p s y c h o t i c s , R o 22-1319 i n t e r a c t s w i t h s t r i a t a l H-spiro­ p e r i d o l b i n d i n g sites i n a sodium-dependent manner (11). O n t h i s basis, R o 22-1319 i s c h a r a c t e r i z e d as a s p e c i f i c D - 2 d o p a m i n e r e c e p t o r a n t a g o ­ nist. In our m o d e l , w e have i n d i c a t e d t h a t a t y p i c a l a n t i p s y c h o t i c s (12) (sulpiride, m e t o c l o p r a m i d e , m o l i n d o n e , a n d R o 22-1319) d i f f e r from c l a s s i c a l n e u r o l e p t i c s ( t r i c y c l i c s , butyrophenones, b u t a c l a m o l , d i p h e n y l piperidines) by l a c k i n g a l i p o p h i l i c f u n c t i o n a l group on the b a s i c n i t r o g e n t h a t c o u l d e x t e n d i n t o the a u x i l i a r y b i n d i n g s i t e i d e n t i f i e d i n our m o d e l . The absence of this l i p o p h i l i c f u n c t i o n a l i t y m a y now be s t a t e d t o be the c h a r a c t e r i s t i c w h i c h distinguishes s e l e c t i v e D - 2 d o p a m i n e r e c e p t o r a n t a g o ­ nists from non-selective antagonists. n

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3

A c o m p a r i s o n of i n v i v o a c t i v i t y a n d H - s p i r o p e r i d o l b i n d i n g i n the p y r r o l o i s o q u i n o l i n e series provides an i n d i c a t i o n of the l i p o p h i l i c i t y r e q u i r e d on the n i t r o g e n s u b s t i t u e n t to r e t a i n D - 2 r e c e p t o r s e l e c t i v i t y . A m o n g the analogs l i s t e d i n T a b l e IV, t h e r e appears to be a break b e t w e e n compounds h a v i n g a l k y l substituents s m a l l e r than p r o p y l i n the Hs p i r o p e r i d o l b i n d i n g assay ( I C ^ > 20 n M ) a n d those w i t h m o r e l i p o p h i l i c groups (propyl or l o n g e r a l k y l , v a r i o u s a r a l k y l ) w i t h I C L Q < 10 n M . F u t h e r studies are i n progress to e v a l u a t e the hypothesis that t h i s break corresponds to the t r a n s i t i o n b e t w e e n s e l e c t i v e D - 2 a n t a g o n i s m and n o n ­ s p e c i f i c (D-1 + D-2) a n t a g o n i s m . The t r a n s i t i o n b e t w e e n D - 2 a n d D - 1 d o p a m i n e r e c e p t o r b i n d i n g a s s o c i a t e d w i t h changes i n l i p o p h i l i c i t y of a b a s i c n i t r o g e n substituent has also been o b s e r v e d f o r the m e t o c l o p r o m i d e analogs Y M - 0 9 1 5 1 - 2 a n d Y M 08050 (13, 14). S i m i l a r l y , i n the t e t r a h y d r o i n d o l o n e s e r i e s , r e p l a c i n g the m o r p h o l i n e r i n g of m o l i n d o n e w i t h a 4 r h y d r o x y - 4 - p h e n y l p i p e r i dine (15) l e a d s to a d r a m a t i c e n h a n c e m e n t of H-spiroperidol binding potency (IC = 0.54 n M vs I C ^ = 74 n M for m o l i n d o n e ) (16). The c h a r a c t e r (»r the a u x i l i a r y b i n d i n g s i t e has been e x p l o r e d f u r t h e r by p r e p a r i n g a series of analogs b e a r i n g h y d r o p h i l i c O H groups i n the side chain (Table V). T h e s e groups w o u l d be e x p e c t e d t o i n t e r f e r e w i t h h y d r o p h o b i c i n t e r a c t i o n s . The trends are c l e a r i n t h a t these h y d r o x y a l k y l analogs are w e a k i n the s p i r o p e r i d o l b i n d i n g assay a n d y e t e x h i b i t potent i n v i v o a c t i v i t y i n a v o i d a n c e . Our p r e d i c t i o n i s that t h e s e compounds are also specific D - 2 receptor antagonists. 5 0

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

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11.

OLSON

Pyrwloisoquinoline

ET AL.

Table V.

E f f e c t of h y d r o p h i l i c groups i n s i d e chain at b a s i c n i t r o g e n on a c t i v i t y .

AVOIDANCE ABD50 COMPOUND

I

α

28

111

Antipsychotics

mg/kg

CH,

CH CH 0H 2

2

po

*H-

SPIROPERIDOL

BINDING nM

0.7

45.5

2.5

90

1.7

96

0.62

41

OH

29

CHCH—(ζ^ 2

30

OH I CH CH-C(CH ) 2

3

3

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

IC50

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272

DOPAMINE

RECEPTORS

S o m e of the p h a r m a c o l o g i c a l l y m o s t potent d e r i v a t i v e s i n our series of p y r r o l o i s o q u i n o l i n e and cycloalkapyrroloisoquinolines are those s u b s t i t u t e d w i t h f l u o r o p h e n y l a c y l groups ( T a b l e VI). T o show that t h i s p o t e n c y i s not the r e s u l t of m a k i n g a h a l o p e r i d o l - t y p e butyrophenone out of our p y r r o l o i s o q u i n o l i n e , the c a r b o n y l group i n 31 was r e d u c e d t o the a l c o h o l (32) and the m e t h y l e n e c h a i n s h o r t e n e d ( c o m p a r e 33 - 35 ). In c o n t r a s t t o the h a l o p e r i d o l - t y p e compounds, i n a l l cases the a l c o h o l s are i n the range of p o t e n c y of the k e t o n e s , a n d s h o r t e n i n g the c h a i n by one c a r b o n has only a m o d e r a t e e f f e c t on p o t e n c y . The b i n d i n g c h a r a c t e r i s t i c s of compounds i n t h i s series and t h e i r a c t i v i t y i n t e s t s i n d i c a t i v e of side e f f e c t s are b e i n g s t u d i e d f u r t h e r .

Table VI.

Fluorophenylacyl and fluorophenylhydroxyalkyl analogs.

AVOIDANCE ABD50 COMPOUND

Χ

η

R

2

R

31

0

3

CH

3

CH

3

0.08

3 2

H.OH

3

CH

3

CH

3

0.15

33

0

3

CH

3

CH CH 2

3

0.20

3 4

0

2

CH

3

CH CH 2

3

0.85

35

0

I

CH

3

CH CH

3

8 p o = 13%

3 6

0

3

(CH )

3

0.15

37

Η,ΟΗ

3

(CH )

3

0.31

3 8

0

3

(CH )

4

0.73

3 9

Η,ΟΗ

3

(CH )

4

1.32

4 0

0

3