Interaction of Phenylisopropylamines with Central 5-HT2 Receptors

Chapter 18 Interaction of Phenylisopropylamines with Central 5-HT2 Receptors Analysis by Quantitative Structure—Activity Relationships Richard A. Glennon and Mark R. Seggel

Downloaded by UNIV LAVAL on July 11, 2016 | http://pubs.acs.org Publication Date: November 14, 1989 | doi: 10.1021/bk-1989-0413.ch018

Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0581 A QSAR investigation of 27 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropane (i.e., 2,5-DMA) reveals that the lipophilic character of the 4-substituent is a primary determining factor for 5-HT2 recept or affinity. The length (size/shape ?) of the substituent may also be important. Previous studies have shown that certain 2,5-DMAs act as 5-HT2 agonists whereas preliminary data suggest others may act as antagonists (or at least as mixed agonist-antagonists). Intrinsic activity may be related to electronic as well as lipo philic properties of the 4-substituent. The discovery of multiple populations of central serotonin receptors (i.e., 5-HT1, 5-HT2, 5-HT3) has ushered in a new era in 5-HT research and has prompted a search for site-selective agents. Recent work from our laboratories has shown that phenalkylamine derivatives bind with varying degrees of affinity and/or selectivity at 5-HT2 sites (1-3) . Because there was evidence that such agents might constitute the first class of 5-HT2-selective agonists, we investigated structureaffinity relationships (SAFIR) for 5-HT2 binding (2,3). It was determined that a primary amine and an a-methyl group (though not necessary) result in optimal affinity. Of various aromatic substituents investigated, optimal, though modest, affinity was associated with a 2,5-dimethoxy substitution pattern (i.e., with 2,5-dimethoxy analogs; 2,5-DMAs). It quickly became evident that 4-substitutents play a significant role in modulating the affinity of the 2,5-DMAs for 5-HT2 sites. For example, introduction of a 4-bromo group, to afford DOB, resulted in a greater than 100-fold increase in affinity; the Ki for the parent 2,5-DMA (1) and for DOB (7) - 5,200 and 41 nM, respectively)(2). In order to determine the role of the 4-substituents, we conducted a Hansch analysis on a series of 13 2,5-DMAs for which we had already obtained binding data. The structures of these agents varied only with respect to the 4-position functionality; in the initial series, R4 - H, OMe, OEt, N02, F, Br, I, Me, Et, n-Pr, n-Bu, t-Bu and n-amyl. A relating equation (Eq 1) suggested that the (X)97-6156/89/0413-0264$06.00/0 © 1989 American Chemical Society

Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989.


18.

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265 Plienylisopropylamine Interaction with 5-HT2

l i p o p h i l i c i t y and t h e e l e c t r o n i c n a t u r e o f t h e 4 - p o s i t i o n s u b s t i t u e n t contributes t o b i n d i n g Q ) . F o r t h e R4 s u b s t i t u e n t s i n q u e s t i o n , t h e Hammett sigma c o n s t a n t 0.4 mg/kg f o r DOBZ, and > 0.2 mg/kg o f DOAM) i n c o m b i n a t i o n w i t h t h e t r a i n i n g dose of DOM (1 mg/kg) p r o d u c e d d i s r u p t i o n o f b e h a v i o r and, t h u s , antago n i s m c o u l d n o t be e v a l u a t e d . On t h e o t h e r hand, t h e 4 - t e r t i a r y butyl derivative (i.e., DOTB, 14) does appear t o p r o d u c e some a n t a g o n i s m (14). A s t u d y was c o n d u c t e d where doses o f DOTB (14) were adminis tered either i n c o m b i n a t i o n w i t h 1 mg/kg o f DOM o r , i n t h e c o n t r o l s t u d i e s , w i t h 1 mL/kg o f 0.9% s a l i n e v e h i c l e . Figure 5 shows that DOTB a t t e n u a t e s the stimulus e f f e c t s o f DOM ( t o a p p r o x i m a t e l y 35% DOM-appropriate r e s p o n d i n g ) . However, a t h i g h doses, DOTB i n combina t i o n w i t h s a l i n e r e s u l t s i n a n i n c r e a s i n g degree o f DOM-like respond i n g ; h i g h e r doses produce d i s r u p t i o n o f b e h a v i o r . These r e s u l t s would s u g g e s t t h a t a t r e l a t i v e l y low doses, DOTB behaves as a 5-HT2 antago n i s t , b u t t h a t a t somewhat h i g h e r doses i t h a s some a g o n i s t proper t i e s . I s DOTB a c t i n g as a mixed a g o n i s t - a n t a g o n i s t ? T h i s i s c u r r e n t l y b e i n g f u r t h e r pursued. N e v e r t h e l e s s , s t u d i e s w i t h i s o l a t e d r a t a o r t a (which s u p p o s e d l y p o s s e s s e s p e r i p h e r a l 5-HT2 r e c e p t o r s ) s u g g e s t t h i s to be t h e c a s e (Roth, Suba, S e g g e l & Glennon, u n p u b l i s h e d d a t a ) . T h i s i s t h e f i r s t QSAR s t u d y o f t h e a f f i n i t y

of phenylisopropyl-



18.

275 Phenylisopropylamine Interaction with 5-HT2

GLENNON & SEGGEL

iY

^

DOM

)

S

T^

0.1

tVyVM

0.15

VYj/V>

0.2

j

,

0.5

As antagonist DOAM

-•>.,.K..y...

0.75

..........

1.0

.....

1.15

1.25

As agonist DOSE

(mg/kg)

F i g u r e 4. R e s u l t s o f s t i m u l u s antagonism and s t i m u l u s general i z a t i o n s t u d i e s w i t h DOAM (15) i n DOM-trained r a t s . (DOAM was a d m i n i s t e r e d 10 min p r i o r t o DOM i n the antagonism s t u d i e s , and i n t h e absence o f DOM i n the agonism s t u d i e s . Doses o f DOAM g r e a t e r t h a n 0.2 and 1.25 mg/kg i n t h e antagonism and agonism studies, r e s p e c t i v e l y , r e s u l t e d i n d i s r u p t i o n of behavior. In the agonism s t u d i e s , 0.5 mg/kg o f DOAM p r o d u c e d 0% DOM-appro p r i a t e responding.)


Magee et al.; Probing Bioactive Mechanisms ACS Symposium Series; American Chemical Society: Washington, DC, 1989. 0.3

1.0

DOSE OF DOTB (mg/kg)

0.6

1.5

2.5

Figure 5. R e s u l t s o f s t i m u l u s antagonism and s t i m u l u s g e n e r a l ization studies with DOTB (14) i n DOM-trained rats. Open triangle represents t h e e f f e c t o f DOM i n t h e absence o f DOTB; s o l i d s q u a r e s r e p r e s e n t t h e e f f e c t o f DOTB a d m i n i s t e r e d 1 min prior t o 1 mg/kg o f DOM (upper curve) or, i n the c o n t r o l s t u d i e s , 1 min p r i o r t o 1 mL/kg o f s a l i n e (lower curve). D disruption o f responding. [A p r e l i m i n a r y a c c o u n t o f t h i s work has been r e p o r t e d (14).]

100 - i



18.

GLENNON & SEGGEL

111 Phenylisopropylamine Interaction with 5-HT2

amine a n a l o g s f o r c e n t r a l 5-HT2 s i t e s . I t would appear t h a t a s s o c i a t e d with the receptor i s a hydrophobic r e g i o n capable o f i n t e r a c t i n g with 4-position substituents o f the phenylisopropylamines. This region seems t o be r e s p o n s i b l e f o r m o d u l a t i n g t h e a f f i n i t y , b u t n o t neces sarily t h e i n t r i n s i c a c t i v i t y , o f t h e 2,5-DMAs. 2,5-DMAs w i t h h y d r o p h i l i c groups a t t h i s p o s i t i o n (e.g.-OH, -NH2) d i s p l a y l i t t l e t o no a f f i n i t y , whereas agents w i t h l i p o p h i l i c groups d i s p l a y h i g h a f f i n i t y ( b u t may l a c k i n t r i n s i c a c t i v i t y ) . I n d o l e a l k y l a m i n e s ( e . g . t r y p t a m i n e analogs) a l s o b i n d a t 5-HT2 s i t e s and we have a t t e m p t e d t o e x p l a i n the s i m i l a r i t i e s i n t h e modes o f b i n d i n g o f these two c l a s s e s o f agents a t 5-HT2 r e c e p t o r s ( 1 5 ) . T h e r e i s e v i d e n c e t h a t p o l a r s u b s t i tuents a t the 7 - p o s i t i o n o f tryptamines decrease their affinity (Table V I I ) (JJ>). In contrast, lipophilic substituents seem t o enhance a f f i n i t y . A 1-methyl group a l s o somewhat enhances affinity (see compound 31, T a b l e V I I ) s u g g e s t i n g t h a t t h e h y d r o p h o b i c r e g i o n might accomodate b o t h t h e 1- a n d 7 - p o s i t i o n o f t h e t r y p t a m i n e s . This has l e d u s t o p r e p a r e s e v e r a l 1 - s u b s t i t u t e d and 7 - s u b s t i t u t e d t r y p t a mine d e r i v a t i v e s f o r purpose o f comparison. Indeed, b o t h t h e 1-amy1 and 7-amyl d e r i v a t i v e s b i n d w i t h g r e a t e r a f f i n i t y t h a n t h e i r unsubs t i t u t e d c o u n t e r p a r t s (16). R e c e n t l y , Cohen and co-workers (17) have also found that 1-substituted indolealkylamines display a higher a f f i n i t y f o r 5-HT2 r e c e p t o r s t h a n t h e i r u n s u b s t i t u t e d d e r i v a t i v e s . Though t h i s i s t h e f i r s t QSAR s t u d y o n 5-HT2 b i n d i n g , several other s t u d i e s have been c o n d u c t e d o n o t h e r a s p e c t s o f p h e n y l i s o p r o p y l a m i n e pharmacology t h a t may have a d i r e c t b e a r i n g on the present results. F o r example, many p h e n y l i s o p r o p y l a m i n e derivatives are hal l u c i n o g e n i c i n humans and we have d e m o n s t r a t e d that a significant

TABLE V I I . A f f i n i t i e s for

o f Several Indolealkylamines 5-HT2 S i t e s N(CH ) 3

2

5-HT A f f i n i t y K i Value (nM) 2

R 28

22 30

11

a

H OH Br H

a

R' H H H CH

3

D a t a from r e f e r e n c e 15. T r i t i a t e d used as r a d i o l i g a n d .

1,200 >10,000 170 400

k e t a n s e r i n was



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PROBING BIOACTIVE MECHANISMS

correlation e x i s t s between t h e human p o t e n c i e s o f t h e s e a g e n t s and b o t h t h e i r d i s c r i m i n a t i o n d e r i v e d p o t e n c i e s and t h e i r a f f i n i t i e s f o r 5-HT2 r e c e p t o r s (2). I n f a c t , we have p r o p o s e d t h a t t h e h a l l u c i n o g e n i c e f f e c t o f t h e p h e n y l i s o p r o p y l a m i n e s i s m e d i a t e d v i a a 5-HT2 agonist i n t e r a c t i o n (2). I n 1975, B a r f k n e c h t e t a l (18) r e p o r t e d that that the octanol-water p a r t i t i o n c o e f f i c i e n t s o f phenylisoprop ylamines i s a n i m p o r t a n t , though n o t n e c e s s a r i l y e x c l u s i v e , d e t e r m i nant o f t h e i r h a l l u c i n o g e n i c potency. U s i n g a s l i g h t l y larger data set, i n c l u d i n g a s e r i e s o f r e a r r a n g e d i s o m e r s , we r e p o r t e d t h a t t h e o v e r a l l l i p o p h i l i c i t y o f t h e s e a g e n t s m i g h t be i m p o r t a n t , but that lipophilicity was p r o b a b l y p r i m a r i l y a r e f l e c t i o n o f t h e l i p o p h i l i c c h a r a c t e r o f the 4 - p o s i t i o n s u b s t i t u e n t s (19). We a l s o d i s c u s s e d t h e importance o f e l e c t r o n i c e f f e c t s ( i . e . , i o n i z a t i o n p o t e n t i a l s ) par t i c u l a r l y f o r those agents l a c k i n g a s i g n i f i c a n t l y l i p o p h i l i c 4-substituent (19). Shulgin and Dyer (22) had a l s o demonstrated a r e l a t i o n s h i p between t h e h a l l u c i n o g e n i c p o t e n c y o f a s m a l l set of 2,5-DMA a n a l o g u e s and t h e l i p o p h i l i c c h a r a c t e r o f t h e i r 4 - p o s i t i o n substituents. S i n c e t h a t time, t h e r e have been a number o f SAR and QSAR s t u d i e s on h a l l u c i n o g e n i c a g e n t s [see Gupta e t a l (21) for a r e v e i w ] , and s e v e r a l o f t h e s e have made m e n t i o n o f t h e l i p o p h i l i c c h a r a c t e r o f t h e 4 - p o s i t i o n s u b s t i t u e n t s . F i n a l l y , t h i s b i n g s u s once a g a i n t o t h e n i t r o compound 4. E a r l y on, we c o n s i d e r e r e d t h e l a c k o f lipophilic character and p o t e n t i a l s i g n i f i c a n c e o f e l e c t r o n i c terms i n e x p l a i n i n g t h e a c t i v i t y o f t h i s agent ( 1 0 ) . We even speculated that weak l i p o p h i l i c c h a r a c t e r might be overshadowed b y e l e c t r o n i c e f f e c t s o f t h e r i n g ( 1 0 ) . L i k e w i s e , G o m e z - J e r i a and co-workers (22) have c o n f i r m e d t h e a c t i v i t y o f t h e n i t r o a n a l o g and have a l s o a r g u e d f o r t h e importance o f an e l e c t r o n i c term i n d e t e r m i n i n g a c t i v i t y . Of course, other f a c t o r s may need t o be c o n s i d e r e d ; f o r example, t h i s p a r t i c u l a r agent may b i n d i n a d i f f e r e n t manner o r t h e n i t r o group may i n f l u e n c e t h e o r i e n t a t i o n o f t h e a d j a c e n t methoxy group r e s u l t i n g i n a " b e t t e r " f i t f o r the molecule than expected. S e v e r a l o t h e r s t u d i e s have examined t h e SAR and QSAR o f t h e s e and various other phenylisopropylamine analogues. I n c l u d e d among t h e s e investigations are t h e i r interactions a t d i f f e r e n t peripheral seroto nin receptors ( e . g . i s o l a t e d r a t fundus, sheep u m b i l i c a l a r t e r y ) ; however, t h e n a t u r e o f t h e r e l a t i o n s h i p between t h e examined 5-HT receptors and 5-HT2 r e c e p t o r s remains, f o r t h e most p a r t , unknown. A number o f t h e s e s t u d i e s have b e e n m e n t i o n e d i n t h e r e v i e w b y Gupta and co-workers (21).

Summary On the b a s i s o f the present s t u d i e s , i t appears t h a t the a f f i n i t y o f the 2,5-DMAs f o r 5-HT2 r e c e p t o r s c a n be a c c o u n t e d f o r , p r i m a r i l y , by the l i p o p h i l i c i t y o f the 4 - p o s i t i o n s u b s t i t u e n t . Other f a c t o r s , par t i c u l a r l y t h o s e d e a l i n g w i t h l e n g t h o r shape, may a l s o p l a y a role. It i s e n t i r e l y p o s s i b l e that the e l e c t r o n i c nature o f the 4 - p o s i t i o n substituents i s also involved i n a f f i n i t y ( a t l e a s t f o r a small sub set o f 2,5-DMA a n a l o g s ) b u t t h i s h a s been more d i f f i c u l t t o demon s t r a t e ; e l e c t r o n i c f a c t o r s may a l s o be i n v o l v e d i n intrinsic acti vity, p a r t i c u l a r l y as i t r e l a t e s t o a l t e r i n g t h e e l e c t r o n r i c h c h a r a c t e r o f t h e a r o m a t i c n u c l e u s o f t h e p h e n y l i s o p r o p y l a m i n e s . The p r e -


18.

GLENNON & SEGGEL

Plienylisopropylamine Interaction with 5-HT2 279

sent studies a l s o have indirect r a m i f i c a t i o n s with regard t o the agonist versus antagonist activity o f phenylis©propylamines, and, a d d i t i o n a l l y , may h e l p e x p l a i n t h e n a t u r e o f t h e i n t e r a c t i o n o f i n d o l e a l k y l a m i n e s w i t h t h e s e same r e c e p t o r s . With the recent demonstra tion that agonists display a greater a f f i n i t y f o r t r i t i a t e d agonistl a b e l e d v e r s u s t r i t i a t e d a n t a g o n i s t - l a b e l e d s i t e s (12), more realis t i c QSAR r e s u l t s might be d e r i v e d u s i n g b i n d i n g d a t a from 5-HT2 s i t e s l a b e l e d w i t h [ H]D0B as r a d i o l i g a n d . Such s t u d i e s a r e a l r e a d y under way.


3

Acknowledgments: These studies were s u p p o r t e d , i n p a r t , b y US PHS g r a n t s DA 01642 and NS 23520. We a l s o w i s h t o e x p r e s s o u r a p p r e c i a tion t o B r y a n Misenheimer and B e t s y Mack f o r t h e i r a s s i s t a n c e i n o b t a i n i n g t h e d r u g d i s c r i m i n a t i o n d a t a and t o Dr. L. B. K i e r f o r helpful d i s c u s s i o n s r e g a r d i n g t h e u s e a n d i n t e r p r e t a t i o n o f t h e con n e c t i v i t y and shape i n d e x e s .

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

15. 16.

Shannon, M.; Battaglia, G.; Glennon, R. A . ; Titeler, M. Eur. J . Pharmacol. 1984, 102, 23-29. Glennon, R. A . ; McKenney, J. D.; Titeler, M. Life Sci. 1984, 35, 2505-2511. Seggel, M. Youssif, M.; Titeler, M.; Lyon, R. A . ; Glennon, R. A. Va. J. Sci. 1986, 37, 122. Hansch, C . ; Leo, A. Substituent Constants for Correlation Analys is in Chemistry and Biology: John Wiley and Sons: New York, 1979 Verloop, A . ; Tipker, J. In QSAR in Drug Design and Technology; Hadzi, D.; Jerman-Blazic, B., Eds.; Elsevier Science: Amsterdam, 1987; pp 97-121. Verloop, A. The STERIMOL Approach to Drug Design; Marcel Dekker: New York, 1987. Hall, L. H. MOLCONN2: A Program for Molecular Topology Analysis; Quincy, MA, 1987. Kier, L. B. Med. Res. Rev. 1987, 7, 417-440. Glennon, R. A. In Transduction Mechanisms of Drug Stimuli; Colpaert, F. C . ; Balster, R., Eds.; Springer-Verlag: Berlin, 1988, pp 16-31. Glennon, R. A . ; Young, R.; Benington, F . ; Morin, R. D. J. Med. Chem. 1982, 25, 1163-1168. Titeler, M.; Herrick, K.; Lyon, R. A; McKenney, J. D.; Glennon, R. A. Eur. J. Pharmacol. 1985, 117, 145-146. Titeler, M.; Lyon, R. A . ; Davis, K. H . ; Glennon, R. A. Biochem. Pharmacol. 1987, 36, 3265-3271. Titeler, M.; Lyon, R. A . ; Glennon, R. A. Psychopharmacology 1988, 94, 213-216. Glennon, R. A. In Clandestinely Produced Drugs, Analogues, and Precursors: Problems and Solutions; Klein, M.; McClain, H . ; Sapienza, F . ; Khan, I . , U.S. Government Printing Office: Washing ton, DC, 1989. Lyon, R. A . ; Titeler, M.; Seggel, M. R.; Glennon, R. A. Eur. J . Pharmacol. 1988, 145, 291-297. Chaurasia, C. S.; Glennon, R. A. Va,. J[. Sci. 1988, 39, 165.


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17. Marzoni, G.; Garbrecht, W. L.; Fludzinski, P.; Cohen, M. L. J. Med. Chem. 1987, 30, 1823-1826. 18. Barfknecht, C. F . ; Nichols, D. E.; Dunn, W. J. III J. Med. Chem. 1975, 18, 208-210. 19. Domelsmith, L. N.; Eaton, T. A . ; Houk, K. N.; Anderson, G. M.; Glennon, R. A . ; Shulgin, A. T . ; Castagnoli, N.; Kollraan, P. A. J. Med. Chem. 1981, 24, 1414-1421. 20. Shulgin, A. T . ; Dyer, D. C. J. Med. Chem. 1975, 18, 1201-1204. 21. Gupta, S. P.; Singh, P.; Bindal, M. C. Chem. Rev. 1983, 83, 633-649. 22. Gomez-Jeria, J . S.; Cassels, B. K.; Saavedra-Aguilar, J . C. Eur. J . Med. Chem. 1987, 22, 433-437. RECEIVED March 30, 1989


Interaction of Phenylisopropylamines with Central 5-HT2 Receptors

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