Zhang_2012_Eur.J.Pharm.Sci_47_813

Nicotinic alpha4beta2* agonists are known to be effective in a variety of preclinical pain models, but the underlying mechanisms of analgesic action are not well-understood. In the present study, we characterized activation and desensitization properties for a set of seventeen novel alpha4beta2*-selective agonists that display druggable physical and pharmacokinetic attributes, and correlated the in vitro pharmacology results to efficacies observed in a mouse formalin model of analgesia. ABT-894 and Sazetidine-A, two compounds known to be effective in the formalin assay, were included for comparison. The set of compounds displayed a range of activities at human (alpha4beta2)(2)beta2 (HS-alpha4beta2), (alpha4beta2)(2)alpha5 (alpha4beta2alpha5) and (alpha4beta2)(2)alpha4 (LS-alpha4beta2) receptors. We report the novel finding that desensitization of alpha4beta2* receptors may drive part of the antinociceptive outcome. Our molecular modeling approaches revealed that when receptor desensitization rather than activation activitiesat alpha4beta2* receptors are considered, there is a better correlation between analgesia scores and combined in vitro properties. Our results suggest that although all three alpha4beta2 subtypes assessed are involved, it is desensitization of alpha4beta2alpha5 receptors that plays a more prominent role in the antinociceptive action of nicotinic compounds. For modulation of Phase I responses, correlations are significantly improved from an r(2) value of 0.53 to 0.67 and 0.66 when HS- and LS-alpha4beta2 DC(50) values are considered, respectively. More profoundly, considering the DC(50) at alpha4beta2alpha5 takes the r(2) from 0.53 to 0.70. For Phase II analgesia scores, adding HS- or LS-alpha4beta2 desensitization potencies did not improve the correlations significantly. Considering the alpha4beta2alpha5 DC(50) value significantly increased the r(2) from 0.70 to 0.79 for Phase II, and strongly suggested a more prominent role for alpha4beta2alpha5 nAChRs in the modulation of pain in the formalin assay. The present studies demonstrate that compounds which are more potent at desensitization of alpha4beta2* receptors display better analgesia scores in the formalin test. Consideration of desensitization propertiesat alpha4beta2* receptors, especially at alpha4beta2alpha5, in multiple linear regression analyses significantly improves correlations with efficacies of analgesia. Thus, alpha4beta2* nicotinic acetylcholine receptor desensitization may contribute to efficacy in the mediation of pain, and represent a mechanism for analgesic effects mediated by nicotinic agonists.