Central cholinergic agents. III. Synthesis of 2-alkoxy-2,8- diazaspiro[4.5]decane-1,3-diones as muscarinic agonists.
A series of 2-alkoxy-2,8-diazaspiro[4.5]decane-1,3-diones and related compounds were synthesized and tested for muscarinic receptor binding affinity using [3H]pirenzepine and [3H]oxotremorine M as ligands. They were also evaluated for agonistic activities in the guinea pig ileum assay. 2-Methoxy- 2,8-diazaspiro[4.5]decane-1,3-dione (1i) was found to be a relatively M1 selective agonist. It reversed CO2-induced impairment of passive avoidance response with long duration of action, but also displayed peripheral effects at low doses. To minimize these side effects, we proposed the idea of conjugation of 1i with a muscarinic antagonist. The carbamate linked conjugate (1u) of 1i with methylatropine was therefore examined.
Ishihara
Y
Y
Chemistry Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Yukimasa
H
H
Miyamoto
M
M
Goto
G
G
D000818:Animals; D001115:Arecoline; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018727:Muscarinic Antagonists; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000502:physiology*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013388:Succinimides / Q000138:chemical synthesis* / Q000494:pharmacology
D018727:Muscarinic Antagonists; D010277:Parasympathomimetics; D010880:Piperidines; D011976:Receptors, Muscarinic; D013141:Spiro Compounds; D013388:Succinimides; D001115:Arecoline