PT  - JOURNAL ARTICLE
AU  - Lu Wenchi Corrie
AU  - Clare Stokes
AU  - Jenny L. Wilkerson
AU  - F. Ivy Carroll
AU  - Lance R. McMahon
AU  - Roger L. Papke
TI  - Nicotinic Acetylcholine Receptor Accessory Subunits Determine the Activity Profile of Epibatidine Derivatives
AID  - 10.1124/molpharm.120.000037
DP  - 2020 Jan 01
TA  - Molecular Pharmacology
PG  - MOLPHARM-AR-2020-000037
4099  - http://molpharm.aspetjournals.org/content/early/2020/07/17/molpharm.120.000037.short
4100  - http://molpharm.aspetjournals.org/content/early/2020/07/17/molpharm.120.000037.full
AB  - Epibatidine is a potent analgetic agent with very high affinity for brain nicotinic acetylcholine receptors (nAChR). We determined the activity profiles of three epibatidine derivatives, RTI-36, RTI-76, and RTI-102, which have affinity for brain nAChR equivalent to that of epibatidine but reduced analgetic activity. RNAs coding for nAChR monomeric subunits and/or concatamers were injected into Xenopusoocytes to obtain receptors of defined subunit composition and stoichiometry. The epibatidine analogs produced protracted activation of high sensitivity (HS) α4- and α2- containing receptors with the stoichiometry of 2alpha:3beta subunits, but not low sensitivity (LS) receptors with the reverse ratio of alpha and beta subunits. Although not strongly activated by the epibatidine analogs, LS α4- and α2- containing receptors were potently desensitized by the epibatidine analogs. In general, the response of α4(2)β2(2)α5and β3α4β2α6β2receptors were similar to those of the HSα4β2receptors. RTI-36, the analog closest in structure to epibatidine, was the most efficacious of the three compounds, also effectively activating α7and α3β4receptors, albeit with lower potency and less desensitizing effects. Although not the most efficacious agonist, RTI-76 was the most potent desensitizer of α4- and α2- containing receptors. RTI-102, a strong partial agonist for HS α4β2receptors, was effectively an antagonist for LS α4β2receptors. Our results highlight the importance of subunit stoichiometry and the presence or absence of specific accessory subunits for determining the activity on these drugs on brain nAChR, confounding the interpretation of in vivo studies, since in most cases these structural details are not known. Significance Statement Epibatidine and related compounds are potent ligands for the high-affinity nicotine receptors of the brain, which are therapeutic targets and mediators of nicotine addiction. Far from being a homogeneous population, these receptors are diverse in subunit composition and vary in subunit stoichiometry. We show the importance of these structural details for drug activity profiles, which create a challenge for the interpretation of in vivo experiments since conventional methods, such as in situ hybridization and immunohistochemistry, cannot illuminate these details.