Allosteric ligands bind to receptors at sites that are distinct from those endogenous agonists and orthosteric pharmacological agents interact with. Both an allosteric and orthosteric ligand bind simultaneously to the receptor to form a ternary complex, where each ligand influences binding affinity of the other to the receptor, either positively or negatively. Allosteric modulators are an intensively studied group of receptor ligands because of their potentially greater selectivity over orthosteric ligands, with the possibility of fine tuning of the effects of endogenous neurotransmitters and hormones. The affinity of an unlabelled allosteric ligand is commonly estimated by measuring its effects on binding of a radio-labelled orthosteric tracer. This scenario is complicated by many folds when one studies the kinetics of interactions of two allosteric agents, added simultaneously, on binding of an orthosteric tracer. In this paper, we provide, for the first time, theoretical basis for analysis of such complex interactions. We have expanded our analysis to include the possibility of having two allosteric modulators interact with the same or different sites on the receptor. An added value of our analysis is to provide a tool to distinguish between the two situations. Finally, we also modelled binding of two molecules of one allosteric modulator to one receptor.

• MeSH
• Allosteric Regulation MeSH
• Allosteric Site MeSH
• Models, Chemical * MeSH
• Kinetics MeSH
• Ligands MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Ligands MeSH

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.

• Keywords
• Alzheimer’s disease, allosteric modulation, muscarinic acetylcholine receptors, schizophrenia,
• Publication type
• Journal Article MeSH
• Review MeSH

Allosteric enhancement of the affinity of muscarinic receptors for their ligands offers a new way to influence cholinergic neurotransmission. The structure of the allosteric binding domain(s) and the features of agonists, antagonists and modulators which determine the occurrence of either positive or negative cooperativity require clarification. We tested interactions between allosteric modulators alcuronium, strychnine and brucine and eight antagonists at muscarinic receptors expressed in CHO cells. In experiments with unlabeled antagonists, all three modulators enhanced the affinity for 4-diphenylacetoxy-N-dimethylpiperidinium (4-DAMP) at the M2 receptors, and strychnine did so also at the M4 receptors. Positive interactions were also observed between alcuronium and L-hyoscyamine (M2) and scopolamine (M2), between strychnine and butylscopolamine (M4), L-hyoscyamine (M2 and M4) and scopolamine (M4), and between brucine and scopolamine (M2). Positive effects of alcuronium, strychnine and brucine on the affinity of the M2 receptors for 4-DAMP have been confirmed by direct measurements of the binding of [3H]-4-DAMP. A comparison of molecular models of several antagonists which are esters revealed that antagonists in which the distance between the N and the carboxyl C atoms corresponds to five chemical bonds are more likely to display positive cooperativity with alcuronium at the M2 receptors than the antagonists in which the N-carboxyl C distance corresponds to four chemical bonds.

• MeSH
• Alcuronium pharmacology   MeSH
• Allosteric Regulation MeSH
• Muscarinic Antagonists chemistry   pharmacology   MeSH
• CHO Cells MeSH
• Cricetinae MeSH
• N-Methylscopolamine metabolism   MeSH
• Piperidines pharmacology   MeSH
• Radioligand Assay MeSH
• Strychnine analogs & derivatives   pharmacology   MeSH
• Tritium MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 4-diphenylacetoxy-1,1-dimethylpiperidinium MeSH Browser
• Alcuronium MeSH
• Muscarinic Antagonists MeSH
• brucine MeSH Browser
• N-Methylscopolamine MeSH
• Piperidines MeSH
• Strychnine MeSH
• Tritium MeSH