Allosteric modulation of alpha 7 nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors (nAChRs) are selective ion channels that belong to the Cys-loop superfamily of ligand-gated ion channels. They are expressed in skeletal muscle, where they mediate muscle contraction, and in the peripheral nervous system, where they mediate ganglionic transmission. NAChRs are also widely expressed in the central nervous system, where they regulate the release of acetylcholine and several other important neurotransmitters. Conventional nAChR agonists, such as acetylcholine, act at an extracellular ‘orthosteric’ binding site, located at the interface between two adjacent subunits. Previous studies have identified a series of positive allosteric modulators (PAMs) that lack agonist activity but which are able to potentiate responses to orthosteric agonists such as acetylcholine. It has been shown, for example, that 4-(1-napthyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulphonamide (TQS) acts as a conventional α7 nAChR PAM. In the present study, evidence has been obtained indicating that a closely related compound, 4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulphonamide (4BP-TQS) is a potent allosteric agonist in both recombinant and native α7 nAChRs. Studies with nAChRs altered by site-directed mutagenesis support the conclusion that allosteric agonists such as 4BP-TQS act via an intra-subunit transmembrane site. Changes in the chemical structure of allosteric modulators have been found to exert profound effects on their pharmacological properties. For example, replacement of the bromine atom in 4BP-TQS with either a chlorine or iodine atom or methyl group (4CP-TQS, 4IP-TQS and 4MP-TQS) results in compounds with pharmacological properties characteristic of allosteric agonists but which display differences in activation rates, inactivation rates and in levels of desensitisation. Further studies conducted with a series of methyl-substituted compounds have provided evidence that molecules interacting with a transmembrane allosteric site can exert diverse pharmacological properties. These include allosteric activation, potentiation of responses to orthosteric agonists and antagonism of orthosteric agonists. These findings highlight the pharmacological diversity of compounds interacting with nAChRs.