title: Analgesic effects mediated by neuronal nicotinic acetylcholine receptor agonists: correlation with desensitization of α4β2* receptors.
abstract: 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)(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.
authors.affiliation: Targacept Inc., Winston-Salem, NC 27101, USA.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Zhang
authors.forename: Yun-De
authors.initials: YD
authors.lastname: Xiao
authors.forename: Kristen G
authors.initials: KG
authors.lastname: Jordan
authors.forename: Phil S
authors.initials: PS
authors.lastname: Hammond
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Van Dyke
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Mazurov
authors.forename: Jason D
authors.initials: JD
authors.lastname: Speake
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lippiello
authors.forename: John W
authors.initials: JW
authors.lastname: James
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Letchworth
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
authors.forename: Terry A
authors.initials: TA
authors.lastname: Hauser
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D045744:Cell Line, Tumor; D005557:Formaldehyde; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D016716:PC12 Cells; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*
chemical_list: D000700:Analgesics; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D005557:Formaldehyde