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Positive Allosteric Modulation of the 7 Nicotinic Acetylcholine Receptor: Ligand Interactions with Distinct Binding Sites and Evidence for a Prominent Role of the M2-M3 Segment

Department of Neuroscience, Centre Médical Universitaire, Geneva, Switzerland (D.B., S.B.); and Neuroscience Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois (S.C., E.G., J.L., M.G.)

The 7 nicotinic acetylcholine receptor (nAChR), a homopentameric, rapidly activating and desensitizing ligand-gated ion channel with relatively high degree of calcium permeability, is expressed in the mammalian central nervous system, including regions associated with cognitive processing. Selective agonists targeting the 7 nAChR have shown efficacy in animal models of cognitive dysfunction. Use of positive allosteric modulators selective for the 7 receptor is another strategy that is envisaged in the design of active compounds aiming at improving attention and cognitive dysfunction. The recent discovery of novel positive allosteric modulators such as 1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea (NS-1738) and 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea (PNU-120596) that are selective for the 7 nAChRs but display significant phenotypic differences in their profile of allosteric modulation, suggests that these molecules may act at different sites on the receptor. Taking advantage of the possibility to obtain functional receptors by the fusion of proteins domains from the 7 and the 5-HT₃ receptor, we examined the structural determinants required for positive allosteric modulation. This strategy revealed that the extracellular N-terminal domain of 7 plays a critical role in allosteric modulation by NS-1738. In addition, 7-5HT₃ chimeras harboring the M2-M3 segment showed that spontaneous activity in response to NS-1738, which confirmed the critical contribution of this small extracellular segment in the receptor gating. In contrast to NS-1738, positive allosteric modulation by PNU-120596 could not be restored in the 7-5HT₃ chimeras but was selectively observed in the reverse 5HT₃-7 chimera. All together, these data illustrate the existence of distinct allosteric binding sites with specificity of different profiles of allosteric modulators and open new possibilities to investigate the 7 receptor function.

Address correspondence to: D. Bertrand, Dept of Neuroscience, CMU, 1, rue Michel Servet, CH-1211 Geneva 4, Switzerland. E-mail: daniel.bertrand{at}medecine.unige.ch

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