Molecular mechanisms and binding site locations for noncompetitive antagonists of nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptors are pentameric proteins that belong to the Cys-loop receptor superfamily. Their essential mechanism of functioning is to couple neurotransmitter binding, which occurs at the extracellular domain, to the opening of the membrane-spanning cation channel. The function of these receptors can be modulated by structurally different compounds called noncompetitive antagonists. Noncompetitive antagonists may act at least by two different mechanisms: a steric and/or an allosteric mechanism. The simplest idea representing a steric mechanism is that the antagonist molecule physically blocks the ion channel. On the other hand, there exist distinct allosteric mechanisms. For example, noncompetitive antagonists may bind to the receptor and stabilize a nonconducting conformational state (e.g., resting or desensitized state), and/or increase the receptor desensitization rate. Barbiturates, dissociative anesthetics, antidepressants, and neurosteroids have been shown to inhibit nicotinic receptors by allosteric mechanisms and/or by open- and closed-channel blockade. Receptor modulation has proved to be highly complex for most noncompetitive antagonists. Noncompetitive antagonists may act by more than one mechanism and at distinct sites in the same receptor subtype. The binding site location for one particular molecule depends on the conformational state of the receptor. The mechanisms of action and binding affinities of noncompetitive antagonists differ among nicotinic receptor subtypes. Knowledge of the structure of the nicotinic acetylcholine receptor, the location of its noncompetitive antagonist binding sites, and the mechanisms of inhibition will aid the design of new and more efficacious drugs for treatment of neurological diseases.