title: Structural differences determine the relative selectivity of nicotinic compounds for native alpha 4 beta 2*-, alpha 6 beta 2*-, alpha 3 beta 4*- and alpha 7-nicotine acetylcholine receptors.
abstract: Mammalian brain expresses multiple nicotinic acetylcholine receptor (nAChR) subtypes that differ in subunit composition, sites of expression and pharmacological and functional properties. Among known subtypes of receptors, alpha 4 beta 2* and alpha 6 beta 2*-nAChR have the highest affinity for nicotine (where * indicates possibility of other subunits). The alpha 4 beta 2*-nAChRs are widely distributed, while alpha 6 beta 2*-nAChR are restricted to a few regions. Both subtypes modulate release of dopamine from the dopaminergic neurons of the mesoaccumbens pathway thought to be essential for reward and addiction. alpha 4 beta 2*-nAChR also modulate GABA release in these areas. Identification of selective compounds would facilitate study of nAChR subtypes. An improved understanding of the role of nAChR subtypes may help in developing more effective smoking cessation aids with fewer side effects than current therapeutics. We have screened a series of nicotinic compounds that vary in the distance between the pyridine and the cationic center, in steric bulk, and in flexibility of the molecule. These compounds were screened using membrane binding and synaptosomal function assays, or recordings from GH4C1 cells expressing h alpha 7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, alpha 4 beta 2*, alpha 6 beta 2*, alpha 7 and alpha 3 beta 4*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at alpha 4 beta 2* and alpha 6 beta 2*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for alpha 6 beta 2*-nAChR.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA. sharon.grady@colorado.edu
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Drenan
authors.forename: Scott R
authors.initials: SR
authors.lastname: Breining
authors.forename: Daniel
authors.initials: D
authors.lastname: Yohannes
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wageman
authors.forename: Nikolai B
authors.initials: NB
authors.lastname: Fedorov
authors.forename: Sheri
authors.initials: S
authors.lastname: McKinney
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004548:Elasticity; D055879:Gene Knock-In Techniques; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; C023666:pyridine