Nicotinic receptors: From protein allostery to computational neuropharmacology
Résumé
We propose an extension and further development of the Monod-Wyman-Changeux model for allosteric transi- tions of regulatory proteins to brain communications and specifically to neurotransmitters receptors, with the nicotinic acetylcholine receptor (nAChR) as a model of ligand-gated ion channels. The present development of- fers an expression of the change of the gating isomerization constant caused by pharmacological ligand binding in terms of its value in the absence of ligands and several “modulation factors”, which vary with orthosteric lig- and binding (agonists/antagonists), allosteric ligand binding (positive allosteric modulators/negative allosteric modulators) and receptor desensitization. The new – explicit – formulation of such “modulation factors”, pro- vides expressions for the pharmacological attributes of potency, efficacy, and selectivity for the modulatory lig- ands (including endogenous neurotransmitters) in terms of their binding affinity for the active, resting, and de- sensitized states of the receptor. The current formulation provides ways to design neuroactive compounds with a controlled pharmacological profile, opening the field of computational neuro-pharmacology.