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Bioisosteric Replacement and Related Analogs in the Design, Synthesis and Evaluation of Ligands for Muscarinic Acetylcholine Receptors

[ Vol. 10 , Issue. 4 ]


Richie R. Bhandare and Daniel J. Canney   Pages 361 - 375 ( 15 )


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.


Bioisostere, oxazolidinone, 1, 3-benzodioxole, tetrahydrofuran, chromones.


Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad St., Philadelphia, PA 19140, USA.

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