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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 Xenopus oocytes 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 responses of α4(2)β2(2)α5 and β3α4β2α6β2 receptors were similar to those of the HS α4β2 receptors. RTI-36, the analog closest in structure to epibatidine, was the most efficacious of the three compounds, also effectively activating α7 and α3β4 receptors, albeit with lower potency and less desensitizing effect. 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 α4β2 receptors, was effectively an antagonist for LS α4β2 receptors. Our results highlight the importance of subunit stoichiometry and the presence or absence of specific accessory subunits for determining the activity of these drugs on brain nAChR, affecting 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 present a challenge for the interpretation of in vivo experiments since conventional methods, such as in situ hybridization and immunohistochemistry, cannot illuminate these details.
Abdrakhmanova,
2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine is a novel potent competitive antagonist of human neuronal alpha4beta2 nAChRs.
2006, Pubmed
Abdrakhmanova,
2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine is a novel potent competitive antagonist of human neuronal alpha4beta2 nAChRs.
2006,
Pubmed Anderson,
Characterization of [3H]ABT-418: a novel cholinergic channel ligand.
1995,
Pubmed Badio,
Epibatidine, a potent analgetic and nicotinic agonist.
1994,
Pubmed Bagdas,
New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on α7 nAChRs.
2018,
Pubmed Campling,
Acute activation, desensitization and smoldering activation of human acetylcholine receptors.
2013,
Pubmed Carbone,
Pentameric concatenated (alpha4)(2)(beta2)(3) and (alpha4)(3)(beta2)(2) nicotinic acetylcholine receptors: subunit arrangement determines functional expression.
2009,
Pubmed
,
Xenbase Carroll,
Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3'-substituted deschloroepibatidine analogues. Novel nicotinic antagonists.
2005,
Pubmed Carroll,
Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues. Novel nicotinic antagonist.
2004,
Pubmed Carroll,
EPIBATIDINE ANALOGS SYNTHESIZED FOR CHARACTERIZATION OF NICOTINIC PHARMACOPHORES-A REVIEW.
2009,
Pubmed Carroll,
Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3'-(substituted phenyl)epibatidine analogues. Nicotinic partial agonists.
2010,
Pubmed Colquhoun,
Activation of ion channels in the frog end-plate by high concentrations of acetylcholine.
1988,
Pubmed Damaj,
Genetic approaches identify differential roles for alpha4beta2* nicotinic receptors in acute models of antinociception in mice.
2007,
Pubmed David,
Biochemical and functional properties of distinct nicotinic acetylcholine receptors in the superior cervical ganglion of mice with targeted deletions of nAChR subunit genes.
2010,
Pubmed
,
Xenbase Drenan,
Cholinergic modulation of locomotion and striatal dopamine release is mediated by alpha6alpha4* nicotinic acetylcholine receptors.
2010,
Pubmed Fowler,
Habenular α5 nicotinic receptor subunit signalling controls nicotine intake.
2011,
Pubmed Gerzanich,
alpha 5 Subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal alpha 3 nicotinic receptors.
1998,
Pubmed
,
Xenbase Gerzanich,
Comparative pharmacology of epibatidine: a potent agonist for neuronal nicotinic acetylcholine receptors.
1995,
Pubmed
,
Xenbase Gerzanich,
"Orphan" alpha6 nicotinic AChR subunit can form a functional heteromeric acetylcholine receptor.
1997,
Pubmed
,
Xenbase Gotti,
Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement.
2010,
Pubmed Grady,
Mouse striatal dopamine nerve terminals express alpha4alpha5beta2 and two stoichiometric forms of alpha4beta2*-nicotinic acetylcholine receptors.
2010,
Pubmed Halevi,
Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
2003,
Pubmed
,
Xenbase Han,
Localization of [3H]nicotine, [3H]cytisine, [3H]epibatidine, and [125I]alpha-bungarotoxin binding sites in the brain of Macaca mulatta.
2003,
Pubmed Han,
Localization of nAChR subunit mRNAs in the brain of Macaca mulatta.
2000,
Pubmed Houghtling,
Characterization of (+/-)(-)[3H]epibatidine binding to nicotinic cholinergic receptors in rat and human brain.
1995,
Pubmed Jackson,
Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice.
2010,
Pubmed Jackson,
The α3β4* nicotinic acetylcholine receptor subtype mediates nicotine reward and physical nicotine withdrawal signs independently of the α5 subunit in the mouse.
2013,
Pubmed Jackson,
The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal.
2009,
Pubmed Jain,
Unorthodox Acetylcholine Binding Sites Formed by α5 and β3 Accessory Subunits in α4β2* Nicotinic Acetylcholine Receptors.
2016,
Pubmed
,
Xenbase KATZ,
A study of the desensitization produced by acetylcholine at the motor end-plate.
1957,
Pubmed Kuryatov,
Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors.
2005,
Pubmed Kuryatov,
Roles of accessory subunits in alpha4beta2(*) nicotinic receptors.
2008,
Pubmed Kuryatov,
Expression of functional human α6β2β3* acetylcholine receptors in Xenopus laevis oocytes achieved through subunit chimeras and concatamers.
2011,
Pubmed
,
Xenbase Kuryatov,
Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses.
2000,
Pubmed
,
Xenbase Li,
The neuronal nicotinic alpha4beta2 receptor has a high maximal probability of being open.
2010,
Pubmed Liu,
Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing α4 and α6 subunits.
2012,
Pubmed Lotfipour,
α2* Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice.
2017,
Pubmed
,
Xenbase Lucero,
Differential α4(+)/(-)β2 Agonist-binding Site Contributions to α4β2 Nicotinic Acetylcholine Receptor Function within and between Isoforms.
2016,
Pubmed
,
Xenbase Luetje,
Both alpha- and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors.
1991,
Pubmed
,
Xenbase Marks,
86Rb+ efflux mediated by alpha4beta2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization.
2010,
Pubmed Marks,
Genetic matters: thirty years of progress using mouse models in nicotinic research.
2013,
Pubmed Moroni,
alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine.
2006,
Pubmed
,
Xenbase Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase Ondachi,
Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2'-fluoro-3'-(substituted pyridinyl)-7-deschloroepibatidine analogues.
2014,
Pubmed
,
Xenbase Papke,
Estimation of both the potency and efficacy of alpha7 nAChR agonists from single-concentration responses.
2006,
Pubmed
,
Xenbase Papke,
Nicotinic acetylcholine receptors: Conventional and unconventional ligands and signaling.
2020,
Pubmed Papke,
Cholinergic Receptors and Addiction.
2020,
Pubmed Papke,
Working with OpusXpress: methods for high volume oocyte experiments.
2010,
Pubmed
,
Xenbase Papke,
The role of the beta 4-subunit in determining the kinetic properties of rat neuronal nicotinic acetylcholine alpha 3-receptors.
1991,
Pubmed
,
Xenbase Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase Papke,
Activation and inhibition of rat neuronal nicotinic receptors by ABT-418.
1997,
Pubmed
,
Xenbase Papke,
Tricks of perspective: insights and limitations to the study of macroscopic currents for the analysis of nAChR activation and desensitization.
2010,
Pubmed
,
Xenbase Papke,
Merging old and new perspectives on nicotinic acetylcholine receptors.
2014,
Pubmed Papke,
Single-channel currents of rat neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
1989,
Pubmed
,
Xenbase Papke,
Similar activity of mecamylamine stereoisomers in vitro and in vivo.
2013,
Pubmed
,
Xenbase Papke,
Activation and inhibition of mouse muscle and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes.
2010,
Pubmed
,
Xenbase Picciotto,
Molecular mechanisms underlying behaviors related to nicotine addiction.
2013,
Pubmed Picciotto,
Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.
1998,
Pubmed Rodriguez,
Discriminative stimulus and hypothermic effects of some derivatives of the nAChR agonist epibatidine in mice.
2014,
Pubmed Sala,
Nicotinic acetylcholine receptors of adrenal chromaffin cells.
2008,
Pubmed Sala,
CC4, a dimer of cytisine, is a selective partial agonist at α4β2/α6β2 nAChR with improved selectivity for tobacco smoking cessation.
2013,
Pubmed Sanjakdar,
Differential roles of α6β2* and α4β2* neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice.
2015,
Pubmed Sine,
Activation of acetylcholine receptors on clonal mammalian BC3H-1 cells by high concentrations of agonist.
1987,
Pubmed Srinivasan,
Nicotine up-regulates alpha4beta2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning.
2011,
Pubmed Stokes,
Looking below the surface of nicotinic acetylcholine receptors.
2015,
Pubmed Stokes,
Use of an α3β4 nicotinic acetylcholine receptor subunit concatamer to characterize ganglionic receptor subtypes with specific subunit composition reveals species-specific pharmacologic properties.
2012,
Pubmed
,
Xenbase Terry,
Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery.
2019,
Pubmed Upton,
α2-Null mutant mice have altered levels of neuronal activity in restricted midbrain and limbic brain regions during nicotine withdrawal as demonstrated by cfos expression.
2015,
Pubmed Wada,
Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat.
1989,
Pubmed
,
Xenbase Xiao,
Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them.
2006,
Pubmed Yang,
Mysterious alpha6-containing nAChRs: function, pharmacology, and pathophysiology.
2009,
Pubmed Zhou,
Human alpha4beta2 acetylcholine receptors formed from linked subunits.
2003,
Pubmed
,
Xenbase Zwart,
5-I A-85380 and TC-2559 differentially activate heterologously expressed alpha4beta2 nicotinic receptors.
2006,
Pubmed
,
Xenbase Zwart,
Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors.
2008,
Pubmed
,
Xenbase
