Allosteric interactions at muscarinic cholinoceptors

Clin Exp Pharmacol Physiol. 1998 Mar-Apr;25(3-4):185-94. doi: 10.1111/j.1440-1681.1998.t01-4-.x.


1. An allosteric interaction occurs when the binding of a ligand to its site on a receptor is able to modify the binding of another ligand to 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 muscarinic cholinoceptors is the ternary complex model, which allows for a three-way interaction between the receptor, a classical (orthosteric) ligand and an allosteric modulator. The interaction may be quantified using 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 versus the unoccupied receptor and is a measure of the magnitude of the cooperativity between two concomitantly bound ligands. 3. Identification of allosteric phenomena requires the utilization of both radioligand binding and functional approaches. Manifestations of allosterism include: (i) a limited ability to influence radioligand binding as the concentration of the latter is increased; (ii) alterations in the dissociation rate of orthosteric ligands; (iii) curvilinear Schild regressions; and (iv) nonadditivity of agonist/orthosteric antagonist/allosteric 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, C7/3'-phth and W84. Alcuronium has proven a most useful pharmacological tool, as it has been shown to display both positive and negative co-operativity, depending on the receptor subtype and orthosteric ligand involved in the interaction. 5. Evidence has accumulated pointing to the existence of a common allosteric binding site 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 cannot be excluded. 6. Allosteric modulators offer a number of potential therapeutic advantages, including a ceiling level to their effects and the possibility of 'absolute selectivity' of action, based on the degree of co-operativity rather than the affinity of the modulator for any one receptor subtype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alcuronium / chemistry
  • Allosteric Regulation
  • Bis-Trimethylammonium Compounds / chemistry
  • Forecasting
  • Gallamine Triethiodide / chemistry
  • Humans
  • Isoindoles
  • Models, Chemical
  • Muscarinic Antagonists / chemistry
  • Neuromuscular Nondepolarizing Agents / chemistry
  • Receptors, Muscarinic / chemistry
  • Receptors, Muscarinic / metabolism*


  • Bis-Trimethylammonium Compounds
  • Isoindoles
  • Muscarinic Antagonists
  • Neuromuscular Nondepolarizing Agents
  • Receptors, Muscarinic
  • heptane-1,7-bis(dimethyl-3'-phthalimidopropylammonium)
  • Gallamine Triethiodide
  • Alcuronium