Allosteric modulation and potential therapeutic applications of heteromeric nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors (nAChRs) have been implicated by behavioral, anatomical and pharmacological studies, in a wide range of neurological pathways and disorders and consequently these receptors are widely viewed as highly promising therapeutic targets for drug development.  nAChRs can be either homomeric or heteromeric, with the heteromeric α4β2 subtype representing the most prevalent neuronal subtype in the CNS.  α4β2 receptor ligands have been shown to be particularly efficacious in animal models of nicotine and drug addiction, cognition and neuropathic pain.  Over the past decade a new drug class has emerged capable of enhancing or attenuating responses induced by agonist stimulation of nAChRs.  These compounds typically act by noncompetitive mechanisms and thus are known as positive or negative allosteric modulators (PAMs and NAMs, respectively).  Many of these PAMs appear similar in action to the benzodiazepine and barbiturate drug classes that act on the structurally related GABA A receptors.  PAMs and NAMs have the potential to provide therapeutic modulation of nAChRs in vivo to treat nicotinic related disorders.  Development of this drug class will require a thorough understanding of the structure-function relationships of these compounds, identification of binding domains and in vivo characterization.  This review will discuss the primary lead compounds identified to date  that allosterically potentiate or inhibit heteromeric nAChRs, including α4β2 and α3β4 subtypes, with a focus on the current understanding of these structural and functional relationships.