15. 10. 1977
1399
Speeialia DISPUTANDUM
S t e r e o s e l e c t i v e a c t i v i t y of chiral n e u r o l e p t i c s * T. G. W h i t e a n d J. S c h m u t z
Research Institute Wander (a Sandoz research unit), P. O. Box 27d7, CH-3001 Berne (Switzerland), 25 February 1977 S u m m a r y . A t t e n t i o n is d r a w n to t h e e v i d e n c e in f a v o u r of t h e stereoselective a c t i v i t y of c h i r a l neuroleptics. T h e results r e p o r t e d b y G u p t a et aI. 1, w h i c h s u g g e s t t h a t t h e i r c h i r a l d i b e n z o t h i e p i n s do n o t fit in w i t h t h a t evidence, are q u e s t i o n e d . T h e s t e r e o s e l e c t i v e a c t i v i t y of c h i r a l rteuroleptics h a s b e e n d e m o n s t r a t e d in 3 cases so far. Of these, b u t a c l a m o l h a s b e e n s t u d i e d in g r e a t e s t d e p t h . P h a r m a c o l o g i c a l * ~, biochemical~, ~, a n d d o p a m i n e r g i c r e c e p t o r b i n d i n g s t u d i e s ~-9 h a v e all s h o w n t h a t t h e n e u r o l e p t i c a c t i o n of b u t a c l a m o l resides in t h e ( + ) , S - e n a n t i o m e r . U s i n g p h a r macological tests (apomorphine- and amphetamine-ant a g o n i s m a n d c a t a l e p t i c a c t i o n in t h e rat), we h a v e d e m o n s t r a t e d 1~ t h a t t h e n e u r o l e p t i c a c t i v i t y of o c t o c l o t h e p i n (1) is d u e t o its ( + ) , S - e n a n t i o m e r . More r e c e n t l y , A s c h w a n d e n e t al. 11 h a v e r e p o r t e d t h a t for t h e d i b e n z o t h i e p i n 2, w h i c h s t r u c t u r a l l y is closely r e l a t e d to octoc l o t h e p i n , i t is a g a i n t h e ( + ) , S - e n a n t i o m e r t h a t is n e u r o l e p t i c a l l y a c t i v e in t h e i r p h a r m a c o l o g i c a l a n d b i o c h e m i c a l models.
CH,CH~
CIH3 (NN] Cl
iN 7
' ""
..N~ "
F
1 (*) -S-Octoclothepin ICH3 H.~2Hs
2 (*) - s
3 (lOS.~'S) 4
CI~'S~
o-o ~
agonist, t h e f r e q u e n c y of o b s e r v a t i o n a n d t h e t e s t d u r a t i o n , for e x a m p l e . I n p a r t i c u l a r , i t could be s u s p e c t e d t h a t t h e p r o l o n g e d o b s e r v a t i o n p e r i o d of 4 h e m p l o y e d m i g h t include non-specific c h a n g e s . T h i s d o u b t receives f u r t h e r s u p p o r t f r o m t h e a u t h o r s ' o w n earlier f i n d i n g s for t h e n e u r o t o x i c effects in t h e r o t a r o d t e s t a n d for t h e i n h i b i t i o n of c o n d i t i o n e d a v o i d ance TM. T h e effective doses were v i r t u a l l y i d e n t i c a l for e a c h p a i r of e n a n t i o m e r s in b o t h tests. F r o m t h i s d a t a we w o u l d deduce, n o t t h a t t h e r e was n o s t e r e o s p e c i f i c i t y in t h e n e u r o l e p t i c a c t i o n of t h e e n a n t i o m e r s , b u t r a t h e r t h a t t h e y l a c k e d a clearly specific n e u r o l e p t i c action. I n t h i s c o n t e x t , we w o u l d also refer t o MetygovA a n d P r o t i v a 14 w h o s t a t e d t h a t t h e lack of s t e r e o s e l e c t i v i t y o r i g i n a l l y r e p o r t e d b y t h e m for o c t o c l o t h e p i n r e l a t e d o n l y t o t h e c e n t r a l d e p r e s s a n t effects, w h e r e a s t h e n e u r o l e p t i c effects were h i g h l y stereospecific.
(1oR, 3'R )
5 (IOR 3'S) 6
(IoS s'R)
I n v i e w of t h i s clear e v i d e n c e for t h e stereospecific act i v i t y of neuroleptics, t h e r e p o r t s b y W i t i a k a n d his associates 1,12, a c c o r d i n g to w h i c h t h e r e are n o s i g n i f i c a n t differences in n e u r o l e p t i c a c t i v i t y b e t w e e n t h e d i b e n z o t h i e p i n e n a n t i o m e r s 3 a n d 4, a n d 5 a n d 6, respectively, are s o m e w h a t surprising. I n t h e m o r e r e c e n t of t h e i r p u b l i c a t i o n s 1, t h e s e a u t h o r s c l a i m t h a t t h e i r results are in a g r e e m e n t w i t h t h o s e originally r e p o r t e d for o c t o c l o t h e p i n (1) b y P r o t i v a a n d co-workers is. T h e y a p p e a r to h a v e o v e r l o o k e d t h e s t a t e m e n t m a d e in o u r r e p o r t o n t h e n e u r o leptic effects of o c t o c l o t h e p i n 10 t h a t t h e Czech workers, in a p e r s o n a l c o m m u n i c a t i o n , h a d c o n f i r m e d o u r findings, a n d t h e i r n e w r e s u l t s c o r r e c t i n g t h e i r earlier claims 13 h a v e since b e e n p u b l i s h e d 1,. B e f o r e s e a r c h i n g for r e a s o n s w h y t h e a m i n o p y r r o l i d i n y l d i b e n z o t h i e p i n s 3 - 6 s h o u l d fail t o c o n f o r m t o tile p a t t e r n , o n e h a s t o b e c e r t a i n t h a t t h e s e s t r u c t u r e s do in f a c t possess specific n e u r o l e p t i c p r o p e r t i e s . R e f e r r i n g t o t h e m o r e r e c e n t r e p o r t b y G u p t a e t al. 1, t h e d e s c r i b e d m e t h o d of m e a s u r i n g a m p h e t a m i n e a n t a g o n i s m is o p e n t o q u e s t i o n . O u r m a i n c r i t i c i s m is t h a t t h e m e t h o d differs i n s e v e r a l i m p o r t a n t r e s p e c t s f r o m a n y of t h e 3 r e f e r e n c e m e t h o d s cited. T h e r e are v a r i o u s m a r k e d differences in t h e dose of
* 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Comments on the publication of Gupta et aI.1. T . K . Gupta, B. R. Vishnuvajjala, D. T. Witiak and M. C. Gerald, Experientia 33, 65 (1977). F.T. Bruderlein and L. G. Humber, J. med. Chem. 18,185 (1975). L.G. Humber and F. T. Bruderlein, Molec. Pharmac. 11, 833 (1975). K. Voith and J. R. Cummings, Can. J. Physiol. Pharmac. 5d, 551 (1975). W. Lippmann, T. Pugsley and J. Merker, Life Sci. 16, 213 (1975). R.J. Miller, A. S. Horn and L. L. Iversen, J. Pbarm. Pharmac. 27, 213 (1975). D.R. Burr, S. J. Enna, I. Creese and S. H. Snyder, Proe. nat. Acad. Sci. USA 72, 4655 (1975). S.J. Enna, J. P. Bennett, Jr, D. R. Burt, I. Creese and S. H. Snyder, Nature 263, 338 (1976). D . R . Burt, I. Creese and S. H. Snyder, Molee. Pharmac. 12, 800 (1976). T. J. Petcher, J. Sehmutz, H. P. Weber and T. G. White, Experientia 31, 1389 (1975). W. Aschwanden, E. Kyburz and P. Seh6nholzer, Helv. ehim. Aeta 59, 1245 (1976). D.T. Witiak, B. R. Vishnuvajjala, T~ K. Gupta and M. C. Gerald, J. med. Chem. 19, 40 (1976). J.O. Jilek, K. ~indelfi~, J. PomykA~ek, O. Horegovsk~r, K. Pelz, E. SvAtek, B. Naked, J. Holubek, J. Mety~ov~ and M. Protiva, Coll. Czech. chem. Commun. 38, 115 (1973). J. Mety~ovg~ and M. Protiva, Activitas herr. sup. (Praha) 77, 218 (1975).
1399
Speeialia DISPUTANDUM
S t e r e o s e l e c t i v e a c t i v i t y of chiral n e u r o l e p t i c s * T. G. W h i t e a n d J. S c h m u t z
Research Institute Wander (a Sandoz research unit), P. O. Box 27d7, CH-3001 Berne (Switzerland), 25 February 1977 S u m m a r y . A t t e n t i o n is d r a w n to t h e e v i d e n c e in f a v o u r of t h e stereoselective a c t i v i t y of c h i r a l neuroleptics. T h e results r e p o r t e d b y G u p t a et aI. 1, w h i c h s u g g e s t t h a t t h e i r c h i r a l d i b e n z o t h i e p i n s do n o t fit in w i t h t h a t evidence, are q u e s t i o n e d . T h e s t e r e o s e l e c t i v e a c t i v i t y of c h i r a l rteuroleptics h a s b e e n d e m o n s t r a t e d in 3 cases so far. Of these, b u t a c l a m o l h a s b e e n s t u d i e d in g r e a t e s t d e p t h . P h a r m a c o l o g i c a l * ~, biochemical~, ~, a n d d o p a m i n e r g i c r e c e p t o r b i n d i n g s t u d i e s ~-9 h a v e all s h o w n t h a t t h e n e u r o l e p t i c a c t i o n of b u t a c l a m o l resides in t h e ( + ) , S - e n a n t i o m e r . U s i n g p h a r macological tests (apomorphine- and amphetamine-ant a g o n i s m a n d c a t a l e p t i c a c t i o n in t h e rat), we h a v e d e m o n s t r a t e d 1~ t h a t t h e n e u r o l e p t i c a c t i v i t y of o c t o c l o t h e p i n (1) is d u e t o its ( + ) , S - e n a n t i o m e r . More r e c e n t l y , A s c h w a n d e n e t al. 11 h a v e r e p o r t e d t h a t for t h e d i b e n z o t h i e p i n 2, w h i c h s t r u c t u r a l l y is closely r e l a t e d to octoc l o t h e p i n , i t is a g a i n t h e ( + ) , S - e n a n t i o m e r t h a t is n e u r o l e p t i c a l l y a c t i v e in t h e i r p h a r m a c o l o g i c a l a n d b i o c h e m i c a l models.
CH,CH~
CIH3 (NN] Cl
iN 7
' ""
..N~ "
F
1 (*) -S-Octoclothepin ICH3 H.~2Hs
2 (*) - s
3 (lOS.~'S) 4
CI~'S~
o-o ~
agonist, t h e f r e q u e n c y of o b s e r v a t i o n a n d t h e t e s t d u r a t i o n , for e x a m p l e . I n p a r t i c u l a r , i t could be s u s p e c t e d t h a t t h e p r o l o n g e d o b s e r v a t i o n p e r i o d of 4 h e m p l o y e d m i g h t include non-specific c h a n g e s . T h i s d o u b t receives f u r t h e r s u p p o r t f r o m t h e a u t h o r s ' o w n earlier f i n d i n g s for t h e n e u r o t o x i c effects in t h e r o t a r o d t e s t a n d for t h e i n h i b i t i o n of c o n d i t i o n e d a v o i d ance TM. T h e effective doses were v i r t u a l l y i d e n t i c a l for e a c h p a i r of e n a n t i o m e r s in b o t h tests. F r o m t h i s d a t a we w o u l d deduce, n o t t h a t t h e r e was n o s t e r e o s p e c i f i c i t y in t h e n e u r o l e p t i c a c t i o n of t h e e n a n t i o m e r s , b u t r a t h e r t h a t t h e y l a c k e d a clearly specific n e u r o l e p t i c action. I n t h i s c o n t e x t , we w o u l d also refer t o MetygovA a n d P r o t i v a 14 w h o s t a t e d t h a t t h e lack of s t e r e o s e l e c t i v i t y o r i g i n a l l y r e p o r t e d b y t h e m for o c t o c l o t h e p i n r e l a t e d o n l y t o t h e c e n t r a l d e p r e s s a n t effects, w h e r e a s t h e n e u r o l e p t i c effects were h i g h l y stereospecific.
(1oR, 3'R )
5 (IOR 3'S) 6
(IoS s'R)
I n v i e w of t h i s clear e v i d e n c e for t h e stereospecific act i v i t y of neuroleptics, t h e r e p o r t s b y W i t i a k a n d his associates 1,12, a c c o r d i n g to w h i c h t h e r e are n o s i g n i f i c a n t differences in n e u r o l e p t i c a c t i v i t y b e t w e e n t h e d i b e n z o t h i e p i n e n a n t i o m e r s 3 a n d 4, a n d 5 a n d 6, respectively, are s o m e w h a t surprising. I n t h e m o r e r e c e n t of t h e i r p u b l i c a t i o n s 1, t h e s e a u t h o r s c l a i m t h a t t h e i r results are in a g r e e m e n t w i t h t h o s e originally r e p o r t e d for o c t o c l o t h e p i n (1) b y P r o t i v a a n d co-workers is. T h e y a p p e a r to h a v e o v e r l o o k e d t h e s t a t e m e n t m a d e in o u r r e p o r t o n t h e n e u r o leptic effects of o c t o c l o t h e p i n 10 t h a t t h e Czech workers, in a p e r s o n a l c o m m u n i c a t i o n , h a d c o n f i r m e d o u r findings, a n d t h e i r n e w r e s u l t s c o r r e c t i n g t h e i r earlier claims 13 h a v e since b e e n p u b l i s h e d 1,. B e f o r e s e a r c h i n g for r e a s o n s w h y t h e a m i n o p y r r o l i d i n y l d i b e n z o t h i e p i n s 3 - 6 s h o u l d fail t o c o n f o r m t o tile p a t t e r n , o n e h a s t o b e c e r t a i n t h a t t h e s e s t r u c t u r e s do in f a c t possess specific n e u r o l e p t i c p r o p e r t i e s . R e f e r r i n g t o t h e m o r e r e c e n t r e p o r t b y G u p t a e t al. 1, t h e d e s c r i b e d m e t h o d of m e a s u r i n g a m p h e t a m i n e a n t a g o n i s m is o p e n t o q u e s t i o n . O u r m a i n c r i t i c i s m is t h a t t h e m e t h o d differs i n s e v e r a l i m p o r t a n t r e s p e c t s f r o m a n y of t h e 3 r e f e r e n c e m e t h o d s cited. T h e r e are v a r i o u s m a r k e d differences in t h e dose of
* 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Comments on the publication of Gupta et aI.1. T . K . Gupta, B. R. Vishnuvajjala, D. T. Witiak and M. C. Gerald, Experientia 33, 65 (1977). F.T. Bruderlein and L. G. Humber, J. med. Chem. 18,185 (1975). L.G. Humber and F. T. Bruderlein, Molec. Pharmac. 11, 833 (1975). K. Voith and J. R. Cummings, Can. J. Physiol. Pharmac. 5d, 551 (1975). W. Lippmann, T. Pugsley and J. Merker, Life Sci. 16, 213 (1975). R.J. Miller, A. S. Horn and L. L. Iversen, J. Pbarm. Pharmac. 27, 213 (1975). D.R. Burr, S. J. Enna, I. Creese and S. H. Snyder, Proe. nat. Acad. Sci. USA 72, 4655 (1975). S.J. Enna, J. P. Bennett, Jr, D. R. Burt, I. Creese and S. H. Snyder, Nature 263, 338 (1976). D . R . Burt, I. Creese and S. H. Snyder, Molee. Pharmac. 12, 800 (1976). T. J. Petcher, J. Sehmutz, H. P. Weber and T. G. White, Experientia 31, 1389 (1975). W. Aschwanden, E. Kyburz and P. Seh6nholzer, Helv. ehim. Aeta 59, 1245 (1976). D.T. Witiak, B. R. Vishnuvajjala, T~ K. Gupta and M. C. Gerald, J. med. Chem. 19, 40 (1976). J.O. Jilek, K. ~indelfi~, J. PomykA~ek, O. Horegovsk~r, K. Pelz, E. SvAtek, B. Naked, J. Holubek, J. Mety~ov~ and M. Protiva, Coll. Czech. chem. Commun. 38, 115 (1973). J. Mety~ovg~ and M. Protiva, Activitas herr. sup. (Praha) 77, 218 (1975).
