| 20114055 |
Grady SR, Drenan RM, Breining SR, Yohannes D, Wageman CR, Fedorov NB, McKinney S, Whiteaker P, Bencherif M, Lester HA, Marks MJ: Structural differences determine the relative selectivity of nicotinic compounds for native alpha4beta2*-, alpha6beta2*-, alpha3beta4*- and alpha7-nicotine acetylcholine receptors. J Physiol. 2009 Mar 15;587(Pt 6):1233-47. Epub 2009 Feb 2.
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, alpha4beta2* and alpha6beta2*-nAChR have the highest affinity for nicotine (where * indicates possibility of other subunits). The alpha4beta2*-nAChRs are widely distributed, while alpha6beta2*-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. alpha4beta2*-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 halpha7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, alpha4beta2*, alpha6beta2*, alpha7 and alpha3beta4*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at alpha4beta2* and alpha6beta2*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for alpha6beta2*-nAChR. |
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