Selectivity of ABT-089 for alpha4beta2* and alpha6beta2* nicotinic acetylcholine receptors in brain.

Numerous pharmaceutical efforts have targeted neuronal nicotinic receptors (nAChRs) for amelioration of cognitive deficits. While alpha4beta2 and alpha7 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 alpha4beta2*-nAChR, ABT-089 had partial agonist activity (7-23% of nicotine) and high selectivity for alpha4alpha5beta2 nAChR as evidenced by loss of activity in thalamus of alpha5(-/-) mice. ABT-089 stimulated [(3)H]-dopamine release (57%) exceeded the activity at alpha4beta2* nAChR, that could be explained by the activity at alpha6beta2* nAChR. The concentration-response relationship for ABT-089 stimulation of alpha6beta2* nAChR was biphasic. EC(50) and efficacy values for ABT-089, respectively, were 28 microM and 98% at the less sensitive alpha6beta2* nAChR and 0.11 microM 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 <or=300 microM at alpha3beta4-nAChR measured by [(3)H]-acetylcholine release from interpeduncular nucleus. Thus, ABT-089 is a beta2* nAChR ligand with demonstrable agonist activity at alpha4beta2* and alpha6beta2* receptors. As one form of alpha6beta2* nAChR is sensitive to sub-muM concentrations, we propose that this receptor in particular may contribute to the enhanced cognitive performance following low doses of ABT-089.