Central nicotinic receptor ligands and pharmacophores

Multiple populations of pentameric nicotinic acetylcholinergic (nACh) receptors exist and several may be classified as central or neuronal. Neuronal nACh receptors, however, are primarily of the α₄β₂ and α₇ types, and these have been the focus of most recent investigations aimed at the development of novel agents and identification of pharmacophores. Selectivity data are limited. Furthermore, because several populations of nACh receptors might indirectly influence a given functional effect, it is difficult to discuss structure–activity relationships (SAR) in terms of differential SAR, or to formulate SAR on the basis of functional studies. For the most part, studies are limited to the formulation of structure–affinity relationships (SAFIR) for the binding of agents at nACh receptors, and for these the α₄β₂ population has been the most extensively investigated. SAFIR and newer agents are reviewed here with reference to earlier studies. Novel agents now have been identified that bind with up to 30 times higher affinity than nicotine and these are providing new insight into the understanding of nACh receptors.