Comparison of the effects of selective and nonselective muscarinic agonists on cognition and thermoregulation in primates.
Peripheral toxicity may explain the disappointing therapeutic effects of nonselective muscarinic agonists in Alzheimer's disease. Partial agonists might exhibit an improved therapeutic index. We compare the central and peripheral cholinergic effects of RS86 with the M1/M3 partial agonists AF 102B and L-689,660 ((-)-3-[2-6 chloropyrazin)yl]-1-azabicyclo[2.2.2]octane) in primates. Administration of RS86 (1.5-2.25 mg/kg i.m.) or L-689,660 (0.1-0.3 mg/kg i.m.), but not AF 102B (up to 6 mg/kg i.m.), caused partial reversal of the disruptive effects of scopolamine on cognition. However, performance remained significantly poorer than in untreated control animals. Adverse effects prevented examination of higher doses. Centrally-mediated hypothermia was induced by RS86 (0.05 mg/kg p.o.) and L-689,660 (0.01 mg/kg p.o.) but only by a high dose of AF 102B (7 mg/kg p.o.). The putative therapeutic advantages of partial M1/M3 agonists over RS86 are discussed.
Rupniak
N M
NM
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Tye
S J
SJ
Iversen
S D
SD
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003071:Cognition / Q000187:drug effects*; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects; D010277:Parasympathomimetics / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011719:Pyrazines; D011812:Quinuclidines / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D012453:Saimiri; D012601:Scopolamine / Q000494:pharmacology; D013028:Space Perception; D013388:Succinimides / Q000494:pharmacology*; D013876:Thiophenes
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010277:Parasympathomimetics; D010879:Piperazines; D011719:Pyrazines; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D013388:Succinimides; D013876:Thiophenes; C076265:L 689660; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; D012601:Scopolamine; C059240:cevimeline