Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists

Psychopharmacology (Berl). 1995 Jan;117(2):208-15. doi: 10.1007/BF02245189.

Abstract

The purpose of the present studies was to compare a novel series of alkoxy-oxazolyl-tetrahydropyridines (A-OXTPs) as muscarinic receptor antagonists. The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2 receptors in brainstem, and [3H]oxotremorine-M to high affinity muscarinic agonist binding sites in cortex. All of the compounds had higher affinity for [3H]pirenzepine than for [3H]QNB or [3H]oxotremorine-M labeled receptors, consistent with an interpretation that they are relatively selective M1 receptor antagonists, although none were as selective as pirenzepine. In addition, dose-response curves were determined for antagonism of oxotremorine-induced salivation (mediated by M3 receptors) and tremor (mediated by non-M1 receptors) in mice. In general, the A-OXTPs were equipotent and equieffective in antagonizing both salivation and tremor, although there were modest differences for some compounds. Dose-response curves also were determined on behavior maintained under a spatial-alternation schedule of food presentation in rats as a measure of effects on working memory. The A-OXTPs produced dose-related decreases in percent correct responding at doses three- to ten-fold lower than those which decreased rates of responding. However, only one compound, MB-OXTP, produced effects on percent correct responding consistent with a selective effect on memory as opposed to non-memory variables. The present results provide evidence that these alkoxy-oxazolyl-tetrahydropyridines are a novel series of modestly M1-selective muscarinic receptor antagonists, and that one member of the series, MB-OXTP, appears to be more selective in its effects on memory than previously studies muscarinic antagonists.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Body Temperature / drug effects
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Male
  • Membranes / drug effects
  • Membranes / metabolism
  • Mice
  • Mice, Inbred Strains
  • Muscarinic Antagonists*
  • Oxazoles / pharmacology*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Rats, Sprague-Dawley
  • Reinforcement Schedule
  • Salivation / drug effects
  • Tremor / chemically induced

Substances

  • Muscarinic Antagonists
  • Oxazoles
  • Pyridines