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Eur J Pharmacol. 2010 Sep 25;643(2-3):218-24. doi: 10.1016/j.ejphar.2010.06.064. Epub 2010 Jul 15.

The subtype-selective nicotinic acetylcholine receptor positive allosteric potentiator 2087101 differentially facilitates neurotransmission in the brain.

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  • 1Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.


Positive allosteric modulators of centrally expressed nicotinic acetylcholine receptors have therapeutic potentials in areas of cognition, motor function and reward. Several chemical classes of allosteric modulators that are selective for alpha7 nicotinic receptors have been characterised, but potentiators for the most widely expressed alpha4beta2 nicotinic receptor subtype are few and less defined, owing probably to the difficulty to achieve selectivity over other heteromeric receptor subtypes. 2087101 (2-amino-5-keto)thiazole) is a potent potentiator of both alpha7 and alpha4beta2 receptors and it has selectivity against the alpha3beta4 subtype, which may be responsible for the undesirable peripheral side effects. To further characterise its ability to differentiate between native nicotinic receptors, we examined the effects of 2087101 on alpha7, alpha4beta2* and alpha3beta4* receptor-mediated responses in the rat brain in electrophysiological and neurochemical experiments. 2087101 significantly potentiated agonist-induced, alpha7 and non-alpha7 receptor-mediated, GABAergic postsynaptic currents in cultured hippocampal neurones, but not the nicotine-stimulated [(3)H]noradrenaline release from hippocampal slices, which was primarily mediated by alpha3beta4* receptors, confirming its selectivity for alpha7 and alpha4beta2* receptors in native systems. 2087101 also significantly enhanced nicotine-stimulated firing increase in dopamine neurones of the ventral tegmental area, an effect that was dihydro-beta-erythroidine-sensitive and thereby mediated by alpha4beta2* nicotinic receptors. 2087101 can therefore enhance native nicotinic activities mediated by alpha7 and alpha4beta2*, but not alpha3beta4* receptors, showing its unique ability to discriminate between native heteromeric nicotinic receptor subtypes and its therapeutic potential for treating brain disorders by concurrent modulation of both alpha7 and alpha4beta2* nicotinic receptors.

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