Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists

Abstract

Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to G(q) family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitter release, temperature homeostasis, and food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachycardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather than muscarinic receptor subtype selectivity.

Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

“…Our results have shown that M3 subtype, but not other muscarinic receptors, mediated the cell proliferation stimulated by exogenous or endogenous ACh. The M3 receptor, which selectively conjugate to the G proteins of the Gq family, could transactivate several second messengers and modulate numerous fundamental functions in central and peripheral nervous system3031. Recent years, increasing evidences demonstrated that M3R may play a vital role in the carcinogenesis of many types of cancer, including colon cancer, lung cancer, and cholangiocarcinoma323334.…”

Molecular Modeling of the M3 Acetylcholine Muscarinic Receptor and Its Binding Site

“…These proteins play a pivotal role in the regulation of many physiological functions both in the central and in the peripheral nervous systems [1]. Like other GPCRs, these proteins exhibit a basal activity that is increased by the action of its natural agonist acetylcholine.…”

“…In the present work, we focus on the human M3 muscarinic acetylcholine receptor (M3R), which is involved in modulation of neurotransmitter release, temperature homeostasis, and food intake in the central nervous system, as well as in the induction of smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle in the peripheral nervous system [1]. M3R is arranged in the distinctive seven-transmembrane (TM) helix bundle architecture like all GPCRs, with its N-terminus located on the extracellular side of the plasma membrane and the C-terminal tail in the cytoplasmic side.…”

Insight into New Potential Targets for the Treatment of Overactive Bladder and Detrusor Overactivity

“…There is still a need for safer M3 antagonists for the treatment of OAB. New selective M3R antagonists currently in early discovery and under development have been designed to address these issues [21]. …”