Synthesis and muscarinic M3 pharmacological activities of 1-azabicyclo[2.2.2]octan-3-one oxime derivatives.
A series of 1-azabicyclo[2.2.2]octan-3-one oximes and related 1-azabicyclo-[2.2.2]-octan-3-one hydroxylamines were synthesized and tested for muscarinic M3 activity. All compounds showed at least some muscarinic binding properties, however, only one member of the series demonstrated mucarinic M3 agonistic properties in vitro (contraction of guinea pig ileum) and in vivo (mydriasis, salivation). In addition, this compound partially reversed the cognitive deficit induced by central cholinergic depletion in two procedures testing memory in the rat, namely the delayed matching to position and swim maze tasks of spatial memory in the rat.
Plate
R
R
Department of Medicinal Chemistry, N.V. Organon, OSS, The Netherlands.
Plaum
M J
MJ
de Boer
T
T
Andrews
J S
JS
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D015878:Mydriasis / Q000139:chemically induced; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D013329:Structure-Activity Relationship
D018721:Muscarinic Agonists; D010091:Oximes; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic