title: Bioisosteric replacement and related analogs in the design, synthesis and evaluation of ligands for muscarinic acetylcholine receptors.
abstract: Previous structure-activity relationship studies involving a series of lactone-based muscarinic ligands identified a lead compound containing a diphenylmethylpiperazine moiety (4; IC50 = 340 nM). The purpose of the present work is to investigate 1,3-benzodioxoles, 4,4-diethyl substituted tetrahydrofurans, 5-substituted oxazolidinones and chromones as bioisosteric replacements for the lactone ring in a novel series of muscarinic ligands. The approach provided compounds with improved % inhibition values and identified a non-selective muscarinic ligand with an IC50 value of 280 nM. The structure-activity relationship for this new series will be discussed. Selected compounds were evaluated in preliminary assays for subtype selectivity and were found to be non-selective.
authors.forename: Richie R
authors.initials: RR
authors.lastname: Bhandare
authors.affiliation: Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad St., Philadelphia, PA 19140, USA. canney@temple.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Canney
mesh_terms: D018678:Cholinergic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007783:Lactones / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018678:Cholinergic Agents; D007783:Lactones; D008024:Ligands; D010879:Piperazines; D011976:Receptors, Muscarinic