Synthesis and Structure-Activity Studies of a Series of Spirooxazolidine-2,4-diones: 4-Oxa Analogues of the Muscarinic Agonist 2-Ethyl-8-methyl-2,8-diazaspirodecane-1,3-dione

Article abstract of DOI:10.1021/jm00068a005

A series of spirooxazolidine-2,4-dione derivatives related to the putative M₁ agonist 2-ethyl-8-methyl-2,8-diazaspiro<4.5>decane-1,3-dione (RS86; 1) were synthesized.The compounds were evaluated as cholinergic agents in in vitro binding assays and in in vivo pharmacological tests including antiamnesic effects using scopolamine-treated mice, hypothermia, and salivation in mice.Four compounds (5a,c,f and 17a) exhibited affinity for cortical M₁ receptors and reversed scopolamine-induced impairment of mouse passive avoidance tasks, as did 1.Among these compounds only 5a exhibited M₁-receptor stimulating activity in pithed rats.Structural requirements for muscarinic activity in this series of spirooxazolidine-2,4-dione derivatives were as strict as those reported for spirocuccinimide derivatives including 1.The antiamnesic dose of 3-ethyl-8-methyl-1-oxo-3,8-diazaspiro<4.5>decane-2,4-dione (5a) was 2 orders of magnitude lower than the doses inducing hypothermia and salivation, in contrast to 1 for which the former dose was only 5-10-fold lower than the latter.These results suggest that the 8-azaspiro<4.5>decane skeleton represents a useful template for designing new muscarinic agonists as antidementia drugs.