Synthesis and structure-activity studies of a series of 1-oxa-2,8-diazaspiro[4.5]decan-3-ones and related compounds as M1 muscarinic agonists.
A series of novel 2,8-dialkyl-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 M1 muscarinic agonists YM796 and RS86, were synthesized by using Michael addition reaction of hydroxyurea or methylhydrazine to alpha, beta-unsaturated esters followed by cyclization reaction. These compounds were assessed for binding affinities for M1 and M2 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 M1 and M2 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 M1 muscarinic receptors. The alteration of the methyl group at N2 of 6a increased the selectivity in binding affinities for M1 over M2 receptors, but resulted in loss of M1 agonistic activity or antiamnesic activity. Compound 13 exhibited only low affinity for M1 receptors, suggesting that a basic nitrogen atom is not tolerated in M1 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.
Tsukamoto
S
S
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Nagaoka
H
H
Igarashi
S
S
Wanibuchi
F
F
Hidaka
K
K
Tamura
T
T
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects; D012472:Salivation / Q000187:drug effects; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014202:Tremor / Q000139:chemically induced
D001372:Aza Compounds; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D013141:Spiro Compounds; D012601:Scopolamine