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-diazaspiro[4.5]decane-1,3-dione.
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 spirosuccinimide derivatives including 1. The antiamnesic dose of 3-ethyl-8-methyl-1-oxa-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.
Tsukamoto
S
S
Neuroscience/Gastrointestinal Research Laboratories, Yamanouchi Institute for Drug Discovery Research, Ibaraki, Japan.
Ichihara
M
M
Wanibuchi
F
F
Usuda
S
S
Hidaka
K
K
Harada
M
M
Tamura
T
T
D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010080:Oxazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D012601:Scopolamine; D013329:Structure-Activity Relationship
D010080:Oxazoles; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D012601:Scopolamine