Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists

• Published in: Psychopharmacology 1995-01, Vol.117 (2), p.208-215
• Main Authors: Shannon, H E, Bymaster, F P, Hendrix, J C, Quimby, S J, Mitch, C H
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/BF02245189

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.