Document Detail


Analgesic effects mediated by neuronal nicotinic acetylcholine receptor agonists: correlation with desensitization of α4β2(∗) receptors.
MedLine Citation:
PMID:  23036283     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Nicotinic 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)2β2 (HS-α4β2), (α4β2)2α5 (α4β2α5) and (α4β2)2α4 (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 DC50 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.
Authors:
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; Terry A Hauser
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-1
Journal Detail:
Title:  European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences     Volume:  -     ISSN:  1879-0720     ISO Abbreviation:  Eur J Pharm Sci     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9317982     Medline TA:  Eur J Pharm Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier B.V.
Affiliation:
Targacept Inc., 200 East First Street, Winston-Salem, NC 27101, USA.
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