Receptors containing α4 and β2 subunits are a major neuronal nicotinic acetylcholine receptor (nAChR) subtype in the brain. This receptor plays a critical role in nicotine addiction, with potential smoking cessation therapeutics producing modulation of α4β2 nAChR. In addition, compounds that act as agonists at α4β2 nAChR may be useful for the treatment of pathological pain. Further, as the α4β2 nAChR has been implicated in cognition, therapeutics that act as α4β2 nAChR agonists are also being examined as treatments for cognitive disorders and neurological diseases that impact cognitive function, such as Alzheimer’s disease and schizophrenia. This review will cover the molecular in vitro evidence that allosteric modulators of the α4β2 neuronal nAChR provide several advantages over traditional α4β2 nAChR orthosteric ligands. Specifically, we explore the concept that nAChR allosteric modulators allow for greater pharmacological selectivity, while minimizing potential deleterious off-target effects. Further, here we discuss the development and preclinical in vivo behavioral assessment of allosteric modulators at the α4β2 neuronal nAChR as therapeutics for smoking cessation, pathological pain, as well as cognitive disorders and neurological diseases that impact cognitive function.
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