Quinuclidinone O-Alkynyloximes with muscarinic agonist activity

Bioorg Med Chem. 2002 Jan;10(1):207-13. doi: 10.1016/s0968-0896(01)00267-x.

Abstract

A series of quinuclidinone O-alkynyloximes (14-19) were synthesized and evaluated in radioligand displacement assays for binding affinities to M1-M3 muscarinic receptors. Radioligand displacement assays were carried out using [3H] oxotremorine-M and [3H] pirenzepine on rat cortical tissue and [3H] N-methylscopolamine on rat heart and submandibulary glands. Two alkynyloximes 15 and 18 had pirenzepine/oxotremorine M ratios which were indicative of muscarinic agonist and partial agonist activity, respectively. They were tested for their mnemonic effects in mice using the swimming escape task and found to attenuate scopolamine induced impairment of the task in mice at 2mg/kg. The results show that the O-alkynyloxime moiety linked to azacycles of appropriate size and rigidity (for example quinuclidine and tropane) is a potentially useful muscarinic pharmacophore that can be exploited for the design of muscarinic agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mice
  • Muscarinic Agonists / chemistry
  • Muscarinic Agonists / pharmacology*
  • Oximes / chemistry
  • Oximes / pharmacology*
  • Quinuclidines / chemistry*
  • Radioligand Assay

Substances

  • Muscarinic Agonists
  • Oximes
  • Quinuclidines