Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

David B. Sattelle , Steven D. Buckingham , Miki Akamatsu , Kazuhiko Matsuda , Ilse Pienaar , Andrew K. Jones , Benedict M. Sattelle , Andrew Almond , Charles D. Blundell

The human α7 nicotinic acetylcholine receptor (nAChR) subunit and its homolog, ACR-16, can generate functional recombinant homomeric receptors when expressed in oocytes. Both nAChRs express robustly in the presence of the co-injected chaperone RIC-3 and show striking differences in the actions of a type I positive allosteric modulator (PAM), ivermectin (IVM). Type I PAMs are characterised by an increase in amplitude only of the response to acetylcholine (ACh), whereas type II PAMs exhibit, in addition, changes in time-course / desensitization of the ACh response. The type I PAMs, ivermectin, 5-hydroxyindole (5-HI), NS-1738 and genistein and the type II PAM, PNU-120596, are all active on human α7 but are without PAM activity on ACR-16, where they attenuate the amplitude of the ACh response. We used the published structure of avermectin B1a to generate a model of IVM, which was then docked into the candidate transmembrane allosteric binding site on α7 and ACR-16 in attempt to gain insights into the observed differences in IVM actions. The new pharmacological findings and computational approaches being developed may inform the design of novel PAM drugs targeting major neurological disorders.

Mots clés: computational modeling; electrophysiology; ivermectin; nicotinic acetylcholine receptor; positive allosteric modulators; ion channels

David B. Sattelle, Steven D. Buckingham, Miki Akamatsu, Kazuhiko Matsuda, Ilse Pienaar, et al.. Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors. Biochemical Pharmacology, 2009, 78 (7), pp.836. ⟨10.1016/j.bcp.2009.06.020⟩. ⟨hal-00509508⟩