Add time:07/27/2019         Source:sciencedirect.com

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.

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