Molecular Docking and ADMET Studies Reveal Therapeutic Potential of the Muscarinic M2 Receptor for CNS and Cardiopulmonary Drug Discovery

Abstract

Muscarinic acetylcholine receptors (mAChRs) regulate a wide range of physiological functions and have been linked to a variety of central nervous system, cardiovascular, genitourinary, gastrointestinal, and respiratory disorders. Because it is involved in several organ systems, the M2 receptor is one of the five mAChR subtypes (M1–M5) that has been investigated the most. Through this analysis we get  insights about the therapeutic potential of M2 receptors by summarizing current understanding about their physiological roles, structure, and signaling pathways. An outline of mAChR categorization and signaling is followed by an explanation of M2-mediated pathways, which include potassium channel and MAP kinase activation as well as the suppression of cAMP synthesis. Based on research using receptor knockout animals, M2 receptor expression and function in the bladder, salivary glands, gastrointestinal system, brain, and heart are described. Molecular docking research of tryptamine and ten other M2 receptor ligands predicted binding modes and affinities, with tryptamine, xanomeline, talsaclidine, and muscarine having the highest affinities. SwissADME  toxicity prediction, distribution, metabolism, excretion, and absorption revealed good safety and pharmacokinetic characteristics. When considered collectively, this review emphasizes the need for subtype-specific medication development as well as the M2 receptor's varied physiological significance. Improved treatments for conditions like Alzheimer's, Parkinson's, chronic obstructive pulmonary disease, irritable bowel syndrome, urinary incontinence, and arrhythmias may result from targeting the M2 receptor utilizing structure-based design techniques. It is necessary to conduct more study on M2 receptor interactions, biased signaling, allosteric regulation, and crystallization with various ligands.