• Jiahui Zhang, Yun-De Xiao, Kristen G Jordan, Phil S Hammond, Katherine M Van Dyke, Anatoly A Mazurov, Jason D Speake, Patrick M Lippiello, John W James, Sharon R Letchworth, Merouane Bencherif, and Terry A Hauser.
• Targacept Inc., Winston-Salem, NC 27101, USA.
• Eur J Pharm Sci. 2012 Dec 18; 47 (5): 813-23.

AbstractNicotinic α4β2* 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 α4β2*-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 (α4β2)(2)β2 (HS-α4β2), (α4β2)(2)α5 (α4β2α5) and (α4β2)(2)α4 (LS-α4β2) receptors. We report the novel finding that desensitization of α4β2* receptors may drive part of the antinociceptive outcome. Our molecular modeling approaches revealed that when receptor desensitization rather than activation activitiesat α4β2* receptors are considered, there is a better correlation between analgesia scores and combined in vitro properties. Our results suggest that although all three α4β2 subtypes assessed are involved, it is desensitization of α4β2α5 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-α4β2 DC(50) values are considered, respectively. More profoundly, considering the DC(50) at α4β2α5 takes the r(2) from 0.53 to 0.70. For Phase II analgesia scores, adding HS- or LS-α4β2 desensitization potencies did not improve the correlations significantly. Considering the α4β2α5 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 α4β2α5 nAChRs in the modulation of pain in the formalin assay. The present studies demonstrate that compounds which are more potent at desensitization of α4β2* receptors display better analgesia scores in the formalin test. Consideration of desensitization propertiesat α4β2* receptors, especially at α4β2α5, in multiple linear regression analyses significantly improves correlations with efficacies of analgesia. Thus, α4β2* nicotinic acetylcholine receptor desensitization may contribute to efficacy in the mediation of pain, and represent a mechanism for analgesic effects mediated by nicotinic agonists.Copyright © 2012 Elsevier B.V. All rights reserved.

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