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Anti-amnesic effects of a novel muscarinic agonist, YM796
Vol.
52, No.s 5 & 6, 1993
Abstracts
589
79 ANTI-AMNESIC
EFFECTS
OF
A
NOVEL
MUSCARINIC
AGONIST,
YM796.
F. W a n i b u c h i , T. N i s h i d a , H. Y a m a s h i t a , K. Hidaka, S. T s u k a m o t o , K. Koshiya and S. Usuda. Central Research Laboratories, Yamanouchi P h a r m a c e u t i c a l Co., Ltd. T s u k u b a , Japan. Accumulating evidence suggests that M 1 muscarinic agonists are possible agents for the symptomatic treatment of d e m e n t i a of A l z h e i m e r type. We h e r e i n r e p o r t the f u r t h e r c h a r a c t e r i z a t i o n of a novel muscarinic agonist, YM796 ( (-)-S-2,8-dimethyl-3-methylene-lo x a - 8 - a z a s p i r o [ 4.5] d e c a n e L-tartrate monohydrate) , compared with o t h e r c h o l i n e r g i c drugs. In vitro, Y M 7 9 6 e x h i b i t e d p r e f e r e n t i a l M 1 agonistic a c t i v i t y and h a d l i t t l e or no a f f i n i t y (Ki > 8 5 ,M) for other neurotransmitter receptors. In vivo, YM796 improved the learning deficit i n d u c e d by s c o p o l a m i n e and the n u c l e u s basalis magnocellularis-lesion at low d o s e s (MED: 0.063 and 0.031 m g / k g po as salt, respectively) , whereas induction of salivation, a p e r i p h e r a l c h o l i n e r g i c r e s p o n s e , r e q u i r e d m u c h h i g h e r d o s e s (ED3^umg = 22 m g / k g po). T h i s s e l e c t i v i t y of Y M 7 9 6 for a n t i - a m n e s i c e f f e c t s was m u c h greater than that of o t h e r cholinergic agents, RS86, A F I 0 2 B and tacrine. YM796 (MED: 0.2 m g / k g po) also i m p r o v e d the c o g n i t i v e i m p a i r m e n t i n d u c e d by e l e c t r o c o n v u l s i v e shock in m i c e but tacrine did not up to 30 m g / k g po. In addition, anti-amnesic efficacy on the rat m o d e l of w o r k i n g m e m o r y was also o b s e r v e d . Thus, YM796 possesses M 1 agonistic activity and p r e f e r e n t i a l l y improves the cognitive impairment in various animal models p r e s u m a b l y by the a c t i v a t i o n of M 1 r e c e p t o r s in the brain. Note) MED; m i n i m u m e f f e c t i v e dose, ED30mg; the d o s e s r e q u i r e d to i n c r e a s e the s a l i v a r y s e c r e t i o n by 30 mg.
88 THE ROLE OF THE MUSCARINIC RECEPTORS SUBTYPES IN SLEEP R E G ~ T I O N P.Angeli*, L.Imeri, S . B i a n c h i and M . M a n c i a , * D i p a r t i m e n t o di Scienze Chimiche, U n i v e r s i t ~ di Camerino, Camerino, Italy a n d I s t i t u t o di F i s i o l o g i a Umana II, U n i v e r s i t ~ di Milano, Milano, Italy Our p r e v i o u s p a p e r s 1,2 s u g g e s t e d that s p e c i f i c m u s c a r i n i c r e c e p t o r subtypes (MI, M 2 a n d M 3) are differentially involved in the cholinergic regulation of t h e sleep-wake cycle, particularly desynchronized sleep (DS) g e n e r a t i o n . D i r e c t i n j e c t i o n of h i g h l y s e l e c t i v e m u s c a r i n i c a n t a g o n i s t s into the p o n t i n e r e t i c u l a r nucleus w e r e p e r f o r m e d in f r e e l y m o v i n g rats, in o r d e r to e l u c i d a t e the anatomical localization of t h e muscarinic receptor subtypes involved in s u c h c o n t r o l . Microinjections of c a r b a c h o l (0.5 ~g dose) i n d u c e d a 52 % i n c r e a s e in DS in 6 hours' recordings of cerebral electric activity (by m e a n s of EEG), o c u l a r m o v e m e n t s (by EOG) and muscular electric activity (by EMG) . M e t h o c t r a m i n e , a highly selective M 2 muscarinic antagonist, induced a significant and d o s e - r e l a t e d d e c r e a s e in the amount of DS (-44 %, - 5 1 % and -68 %) a n d an i n c r e a s e in DS l a t e n c y (+123 %, +150 % and +345 %) in c o m p a r i s o n to c o n t r o l condition, f o l l o w i n g a d m i n i s t r a t i o n of 5, i0 and 15 ~g doses, r e s p e c t i v e l y , in 6 hours' recordings. The p r e s e n t r e s u l t s s u g g e s t that p o n t i n e m u s c a r i n i c M2 r e c e p t o r s are n e c e s s a r y for DS g e n e r a t i o n and m a i n t e n a n c e . References. IL. Imeri et al., 2L. Imeri et al.,
NeuroReport, NeuroReport,
2:383-385, 3:276-278,
1991. 1992.
52, No.s 5 & 6, 1993
Abstracts
589
79 ANTI-AMNESIC
EFFECTS
OF
A
NOVEL
MUSCARINIC
AGONIST,
YM796.
F. W a n i b u c h i , T. N i s h i d a , H. Y a m a s h i t a , K. Hidaka, S. T s u k a m o t o , K. Koshiya and S. Usuda. Central Research Laboratories, Yamanouchi P h a r m a c e u t i c a l Co., Ltd. T s u k u b a , Japan. Accumulating evidence suggests that M 1 muscarinic agonists are possible agents for the symptomatic treatment of d e m e n t i a of A l z h e i m e r type. We h e r e i n r e p o r t the f u r t h e r c h a r a c t e r i z a t i o n of a novel muscarinic agonist, YM796 ( (-)-S-2,8-dimethyl-3-methylene-lo x a - 8 - a z a s p i r o [ 4.5] d e c a n e L-tartrate monohydrate) , compared with o t h e r c h o l i n e r g i c drugs. In vitro, Y M 7 9 6 e x h i b i t e d p r e f e r e n t i a l M 1 agonistic a c t i v i t y and h a d l i t t l e or no a f f i n i t y (Ki > 8 5 ,M) for other neurotransmitter receptors. In vivo, YM796 improved the learning deficit i n d u c e d by s c o p o l a m i n e and the n u c l e u s basalis magnocellularis-lesion at low d o s e s (MED: 0.063 and 0.031 m g / k g po as salt, respectively) , whereas induction of salivation, a p e r i p h e r a l c h o l i n e r g i c r e s p o n s e , r e q u i r e d m u c h h i g h e r d o s e s (ED3^umg = 22 m g / k g po). T h i s s e l e c t i v i t y of Y M 7 9 6 for a n t i - a m n e s i c e f f e c t s was m u c h greater than that of o t h e r cholinergic agents, RS86, A F I 0 2 B and tacrine. YM796 (MED: 0.2 m g / k g po) also i m p r o v e d the c o g n i t i v e i m p a i r m e n t i n d u c e d by e l e c t r o c o n v u l s i v e shock in m i c e but tacrine did not up to 30 m g / k g po. In addition, anti-amnesic efficacy on the rat m o d e l of w o r k i n g m e m o r y was also o b s e r v e d . Thus, YM796 possesses M 1 agonistic activity and p r e f e r e n t i a l l y improves the cognitive impairment in various animal models p r e s u m a b l y by the a c t i v a t i o n of M 1 r e c e p t o r s in the brain. Note) MED; m i n i m u m e f f e c t i v e dose, ED30mg; the d o s e s r e q u i r e d to i n c r e a s e the s a l i v a r y s e c r e t i o n by 30 mg.
88 THE ROLE OF THE MUSCARINIC RECEPTORS SUBTYPES IN SLEEP R E G ~ T I O N P.Angeli*, L.Imeri, S . B i a n c h i and M . M a n c i a , * D i p a r t i m e n t o di Scienze Chimiche, U n i v e r s i t ~ di Camerino, Camerino, Italy a n d I s t i t u t o di F i s i o l o g i a Umana II, U n i v e r s i t ~ di Milano, Milano, Italy Our p r e v i o u s p a p e r s 1,2 s u g g e s t e d that s p e c i f i c m u s c a r i n i c r e c e p t o r subtypes (MI, M 2 a n d M 3) are differentially involved in the cholinergic regulation of t h e sleep-wake cycle, particularly desynchronized sleep (DS) g e n e r a t i o n . D i r e c t i n j e c t i o n of h i g h l y s e l e c t i v e m u s c a r i n i c a n t a g o n i s t s into the p o n t i n e r e t i c u l a r nucleus w e r e p e r f o r m e d in f r e e l y m o v i n g rats, in o r d e r to e l u c i d a t e the anatomical localization of t h e muscarinic receptor subtypes involved in s u c h c o n t r o l . Microinjections of c a r b a c h o l (0.5 ~g dose) i n d u c e d a 52 % i n c r e a s e in DS in 6 hours' recordings of cerebral electric activity (by m e a n s of EEG), o c u l a r m o v e m e n t s (by EOG) and muscular electric activity (by EMG) . M e t h o c t r a m i n e , a highly selective M 2 muscarinic antagonist, induced a significant and d o s e - r e l a t e d d e c r e a s e in the amount of DS (-44 %, - 5 1 % and -68 %) a n d an i n c r e a s e in DS l a t e n c y (+123 %, +150 % and +345 %) in c o m p a r i s o n to c o n t r o l condition, f o l l o w i n g a d m i n i s t r a t i o n of 5, i0 and 15 ~g doses, r e s p e c t i v e l y , in 6 hours' recordings. The p r e s e n t r e s u l t s s u g g e s t that p o n t i n e m u s c a r i n i c M2 r e c e p t o r s are n e c e s s a r y for DS g e n e r a t i o n and m a i n t e n a n c e . References. IL. Imeri et al., 2L. Imeri et al.,
NeuroReport, NeuroReport,
2:383-385, 3:276-278,
1991. 1992.