SCH 57790, a selective muscarinic M(2) receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals.
The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.
Carey
G J
GJ
Pharmacia Corp., 301 Henrietta St., Kalamazoo, MI 49007, USA. galen.j.carey@pharmacia.com
Billard
W
W
Binch
H
H
Cohen-Williams
M
M
Crosby
G
G
Grzelak
M
M
Guzik
H
H
Kozlowski
J A
JA
Lowe
D B
DB
Pond
A J
AJ
Tedesco
R P
RP
Watkins
R W
RW
Coffin
V L
VL
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D003071:Cognition / Q000187:drug effects*; D006224:Cricetinae; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D017551:Microdialysis; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012453:Saimiri; D012601:Scopolamine / Q000494:pharmacology; D013997:Time Factors
D018727:Muscarinic Antagonists; D010879:Piperazines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C117900:SCH 57790; D012601:Scopolamine; D000109:Acetylcholine