Synthesis and Structure-Activity Studies of a Series of 1-Oxa-2,8-diazaspiro[4.5]decan-3-ones and Related Compounds as M_1 Muscarinic Agonists

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A series of novel 2,8-dialykl-1-oxa-2,8-diazaspiro[4.5]decan-3-ones and 2,8-dimethyl-1,2,8-triazaspiro[4.5]-decan-3-one (13), related to M_1 muscarinic agonists YM796 and RS86,were synthesized by using Michael addition reaction of hydroxyurea or methylhydrazine to α, β-unsaturated esters followed by cyclization reaction. These compounds were assessed for binding affinities for M_1 and M_2 receptors and in vivo muscarinic activity : namely, amelioration of scopolamine-induced impairment in rat passive avoidance tasks and induction of hypothermia, tremor, and salivation. 2,8-Dimethyl-1-oxa-2,8-diazaspiro[4.5]decan-3-one (6a) exhibited high affinities for both M_1 and M_2 receptors, showed antiamnesic activity (0.1 mg/kg, s.c.) and induced hypothermia (3 mg/kg, s.c.). In addition, 6a stimulated phosphoinositide hydrolysis in rat hippocampal slices, indicating partial agonistic activity for M_1 muscarinic receptors. The alteration of the methyl group at N2 of 6a increased the selectivity in binding affinities for M_1 over M_2 receptors, but resulted in loss of M_1 agonistic activity or antiamnesic activity. Compound 13 exhibited only low affinity for M_1 receptors, suggesting that a basic nitrogen atom is not tolerated in M_1 receptor binding as a substitute for an oxygen atom or a carbonyl group at the 1-position of 6a or RS86. None of these derivatives exhibited high selectivity for antiamnesic effect over induction of hypothermia compared to YM796.
社団法人日本薬学会の論文
1995-09-15

Synthesis and Structure-Activity Studies of a Series of 1-Oxa-2,8-diazaspiro[4.5]decan-3-ones and Related Compounds as M_1 Muscarinic Agonists

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