ALLOSTERIC INTERACTIONS AT MUSCARINIC CHOLINOCEPTORS

1. An allosteric interaction occurs when the binding of a ligand to it s site on a receptor is able to modify the binding of another ligand t o a topographically distinct site on the same receptor and vice versa, The muscarinic cholinoceptors represent the best-studied examples of allosteric phenomena among the G-protein-coupled receptor superfamily, 2. The simplest model describing allosteric interactions at muscarini c cholinoceptors is the ternary complex model, which allows for a thre e-way interaction between the receptor, a classical (orthosteric) liga nd and an allosteric modulator, The interaction may be quantified usin g the dissociation constant of each ligand for its respective binding site on the free receptor and the 'co-operativity factor' alpha, This latter term is the ratio of affinities of a ligand for the occupied ve rsus the unoccupied receptor and is a measure of the magnitude of the cooperativity between two concomitantly bound ligands, 3, Identificati on of allosteric phenomena requires the utilization of both radioligan d binding and functional approaches, Manifestations of allosterism inc lude: (i) a limited ability to influence radioligand binding as the co ncentration of the latter is increased; (ii) alterations in the dissoc iation rate of orthosteric ligands; (iii) curvilinear Schild regressio ns; and (iv) nonadditivity of agonist/orthosteric antagonist/allosteri c modulator combination concentration ratios, 4. Allosteric modulators of muscarinic cholinoceptors represent a diverse range of compounds, Some of the most studied agents include gallamine, alcuronium and the bis-ammonium compounds, C-7/3'-phth and W84, Alcuronium has proven a m ost useful pharmacological teal, as it has been shown to display both positive and negative co-operativity, depending on the receptor subtyp e and orthosteric ligand involved in the interaction, 5. Evidence has accumulated pointing to the existence of a common allosteric binding s ite on the muscarinic cholinoceptors, located close to the orthosteric site, but at a more extracellular level, however, the possibility of more than one accessory binding site on various receptor subtypes cann ot be excluded, 6. Allosteric modulators offer a number of potential t herapeutic advantages, including a ceiling level to their effects and the possibility of 'absolute selectivity' of action, based on the degr ee of co-operativity rather than the affinity of the modulator for any one receptor subtype.