Papke_2011_J.Pharmacol.Exp.Ther_337_367

Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of alpha4beta2* [(alpha4)(2)(beta2)(3), (alpha4)(3)(beta2)(2), and (alpha4)(2)(beta2)(2)alpha5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of alpha7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, "run-up" of alpha7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of alpha7 responses by alpha4beta2 partial agonists and decreases in alpha4beta2* responses by alpha7-selective agonists. These data indicate the dual effects expected for alpha4beta2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development.