Selectivity of ABT-089 for α4β2*and α6β2*nicotinic acetylcholine receptors in brain

Numerous pharmaceutical efforts have targeted neuronal nicotinic receptors (nAChRs) for amelioration of cognitive deficits. While alpha 4 beta 2 and alpha 7 are the more prominent nAChR in brain, other heteromeric nAChR can have important impact on agonist pharmacology. ABT-089 is a pioneer nAChR agonist found to enhance cognitive function with an exceptionally low incidence of adverse effects. To further investigate the mechanism of action of ABT-089, we evaluated its function in mouse brain preparations in which we have characterized the subunit composition of native nAChR. Among alpha 4 beta 2*-nAChR, ABT-089 had partial agonist activity (7-23% of nicotine) and high selectivity for alpha 4 alpha 5 beta 2 nAChR as evidenced by loss of activity in thalamus of alpha 5(-/-) mice. ABT-089 stimulated [(3)H]-dopamine release (57%) exceeded the activity at alpha 4 beta 2* nAChR, that could be explained by the activity at alpha 6 beta 2* nAChR. The concentration-response relationship for ABT-089 stimulation of alpha 6 beta 2* nAChR was biphasic. EC(50) and efficacy values for ABT-089, respectively, were 28 mu M and 98% at the less sensitive alpha 6 beta 2* nAChR and 0.11 mu M and 36% at the more sensitive Subtype (the most sensitive target for ABT-089 identified to date). ABT-089 had essentially no agonist or antagonist activity at concentrations <= 300 mu M at alpha 3 beta 4-nAChR measured by [(3)H]-acetylcholine release from interpeduncular nucleus. Thus, ABT-089 is a beta 2* nAChR ligand with demonstrable agonist activity at alpha 4 beta 2* and alpha 6 beta 2* receptors. As one form of alpha 6 beta 2* nAChR is sensitive to sub-mu M concentrations, we propose that this receptor in particular may contribute to the enhanced cognitive performance following low doses of ABT-089. (C) 2009 Elsevier Inc. All rights reserved.