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

J Med Chem. 1993 Aug 6;36(16):2292-9. 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 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.

MeSH terms

  • Amnesia / chemically induced
  • Amnesia / prevention & control
  • Animals
  • Male
  • Mice
  • Mice, Inbred ICR
  • Oxazoles / chemical synthesis*
  • Oxazoles / metabolism
  • Oxazoles / pharmacology*
  • Parasympathomimetics / analogs & derivatives
  • Parasympathomimetics / chemical synthesis*
  • Parasympathomimetics / metabolism
  • Parasympathomimetics / pharmacology*
  • Rats
  • Receptors, Muscarinic / metabolism
  • Scopolamine
  • Structure-Activity Relationship


  • Oxazoles
  • Parasympathomimetics
  • Receptors, Muscarinic
  • Scopolamine