Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists |
| |
Authors: | H E Shannon F P Bymaster J C Hendrix S J Quimby C H Mitch |
| |
Institution: | (1) Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, 46285 Indianapolis, IN, USA |
| |
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-oxazolyltetrahydropyridines 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 studied muscarinic antagonists. |
| |
Keywords: | Muscarinic antagonists Scopolamine Trihexyphenidyl Tremor Salivation Working memory Spatial alternation behavior Mice Rats |
本文献已被 SpringerLink 等数据库收录! |
|