Pharmacological studies on novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives, YM796 and YM954.
We have investigated the pharmacological profiles of the novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives, YM796 (2,8-dimethyl-3-methylene) and YM954 (2-ethyl-8-methyl-3-oxo). These compounds, like the putative M1 agonists, RS86 and AF102B, inhibited [3H]pirenzepine binding to cerebral cortical membranes in the micromolar range and weakly inhibited [3H]quinuclidinyl benzylate binding to cerebellar membranes. Their (-) isomers had Hill coefficients lower than 1.0. (+/-)-YM796, (+/-)-YM954 and RS86, but not AF102B, stimulated phosphoinositide hydrolysis in hippocampal slices, an effect which is mainly linked to M1 receptors. (+/-)-YM796 (0.031 mg/kg p.o.) and (+/-)-YM954 (0.016 mg/kg p.o.) reversed the cognitive impairment in nucleus basalis magnocellularis-lesioned rats in a passive avoidance task more effectively than did RS86 and AF102B. Similar results were obtained in scopolamine-treated rats. Finally, (+/-)-YM796 was weaker than (+/-)-YM954 and RS86 in the induction of tremor, hypothermia and contraction of isolated ileum, which are mainly mediated by M2 and/or M3 receptors. These results suggest that (+/-)-YM796, (+/-)-YM954 and RS86 have M1 agonistic activity in central nervous system and that (+/-)-YM796 has relatively weak M2 and/or M3 agonistic activity.
Wanibuchi
F
F
Central Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Konishi
T
T
Harada
M
M
Terai
M
M
Hidaka
K
K
Tamura
T
T
Tsukamoto
S
S
Usuda
S
S
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010277:Parasympathomimetics / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012601:Scopolamine / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*; D013388:Succinimides / Q000494:pharmacology; D013876:Thiophenes; D014202:Tremor / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
C067766:2,8-dimethyl-3-methylene-1-oxa-8-azaspiro(4,5)decane; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D013141:Spiro Compounds; D013388:Succinimides; D013876:Thiophenes; C067767:2-ethyl-8-methyl-3-oxo-1-oxa-8-azaspiro(4,5)decane; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; D012601:Scopolamine; C059240:cevimeline