Muscarinic activity of the thiolactone, lactam, lactol, and thiolactol analogs of pilocarpine and a hypothetical model for the binding of agonists to the M1 receptor

Abstract

Pilocarpine isosteres have been synthesized and characterized with regard to their in vitro muscarinic properties. The results indicate that the carbonyl oxygen of the lactone function of pilocarpine is of primary importance for agonist activity with the ether oxygen being of lesser or secondary importance. An X-ray structure determination for the hydrogen O,O'-ditoluoyltartrate salt of thiolactone pilocarpine isostere 2a has been performed. This compound has an unusual pharmacological profile exhibiting M1-agonist selectivity as well ass presynaptic antagonism. As a result this compound is also viewed as having therapeutic potential for Alzheimer's disease. A model for the binding of pilocarpine and other muscarinic agonists to the third transmembrane helix of the human m1 muscarinic receptor has been developed.

Modifications to five-substituted 3,3-diethyl-4,5-dihydro-2(3H)-furanones en route to novel muscarinic receptor ligands

“…In recent years, molecular modeling and computational approaches have been used also to aid in the design of muscarinic ligands (Shapiro et al, 1992;Nordvall and Hacksell, 1993;Peng et al, 2006;Johren and Holtje, 2002;Ostopovici et al, 2007). For example, 3D molecular modeling techniques and docking studies using a homology model of bovine rhodopsin have revealed unique interactions between acetylcholine (ACh) and the binding pockets of M 1 -M 5 receptors (Pedretti et al, 2006).…”

Ranitidine analog, JWS-USC-75IX, enhances memory-related task performance in rats

“…For example, selective M 2 receptor antagonists such as BIBN-99 [Doods et al, 1993, Quirion et al, 1995 and AF-DX 116, [Lapchak et al, 1989;Packard et al, 1990], have been reported to increase synaptic acetylcholine levels and improve the performance of memory tasks in rodents. Several oxotremorine analogs [e.g., BM-5;Engstrom et al, 1987] and pilocarpine isosteres [e.g., thiopilocarpine; Shapiro et al, 1992] exhibit M 1 agonist activity as well as M 2 antagonist properties and are of potential value.…”

A Green Route for the Synthesis of Antiepileptic Drug Losigamone and Its Analogues

“…在筛选氯西加酮所做的系统构效研究中没有考虑 到分子中 4-羟乙酰乙酸内酯部分的重要性. 研究表明, 利用电子等排原理将某些化合物内酯部分替换为硫代 内 酯 表 现 出 来 相 似 的 或 者 更 好 的 药 理 活 性 , 例 如 thiopilocarpin [8] , thiobasidalin [9] 和 thioascorbic acid [10] . 因 …”