Allosteric Modulation of Muscarinic Acetylcholine Receptors

Abstract

An allosteric modulator is a ligand that binds to an allosteric site on the receptor and changes receptor conformation to produce increase (positive cooperativity) or decrease (negative cooperativity) in the binding or action of an orthosteric agonist (e.g., acetylcholine). Since the identification of gallamine as the first allosteric modulator of muscarinic receptors in 1976, this unique mode of receptor modulation has been intensively studied by many groups. This review summarizes over 30 years of research on the molecular mechanisms of allosteric interactions of drugs with the receptor and for new allosteric modulators of muscarinic receptors with potential therapeutic use. Identification of positive modulators of acetylcholine binding and function that enhance neurotransmission and the discovery of highly selective allosteric modulators are mile-stones on the way to novel therapeutic agents for the treatment of schizophrenia, Alzheimer’s disease and other disorders involving impaired cognitive function.

Structural Insight into Specificity of Interactions between Nonconventional Three-finger Weak Toxin from Naja kaouthia (WTX) and Muscarinic Acetylcholine Receptors

“…First, the negative binding cooperativity between WTX and another orthosteric ligand, acetylcholine, was previously observed at M1, M2, M4, and M5 mAChRs (15). Second, it is well documented that minor changes in the structure of allosteric modulators may lead to a completely different sort of cooperativity (6). For example, the changes in mode of interaction with acetylcholine or NMS binding at different subtypes of mAChR were described for a series of strychnine and brucine analogues (41).…”

“…Separate groups of three-finger toxins act on numerous targets (2), including two classes of acetylcholine receptors as follows: nicotinic acetylcholine receptors (nAChRs) 2 belonging to ligand-gated ion channels (3) and muscarinic acetylcholine receptors (mAChRs) of the G protein-coupled receptor (GPCR) family (4). Both types of acetylcholine receptors are responsible for cholinergic signaling in central and peripheral nervous systems and could be considered as promising targets for treatment of a number of disorders, including Alzheimer disease, schizophrenia, and Parkinson disease and chronic obstructive pulmonary disease (3,5,6).…”

Structure and Function of GPCRs

“…Their function involves the increase of exocrine secretions, contraction of the cardiac and smooth muscles in the gastrointestinal tract and lung and reduction of the heart rate. They are important for learning, memory and attention mechanisms, motor control, nociception and regulation of the sleep-wake cycle (Jakubík and El-Fakahany, 2010). Muscarinic receptors belong to the family of Rhodopsin-like G protein-coupled receptors (GPCRs) (Lagerström and Schiöth, 2008).…”

On homology modeling of the M2 muscarinic acetylcholine receptor subtype

“…However, simple homology modeling is with high probability unsuitable for modeling of ligand binding that induce large conformational change (e.g. muscarinic allosteic modulators; for a review see [2]). As noted above success or failure of simple homology modeling is determined by the suitability of the template(s).…”

“…Over the last two decades, intensive research in the field of muscarinic receptors has resulted in the discovery of new compounds that interact with muscarinic receptors in a novel manner [2]. Several of them exhibit unusual behaviors that do not mimic known orthosteric competitive agonists and antagonists.…”