Synthesis, receptor binding and QSAR studies on 6-substituted nicotine derivatives as cholinergic ligands

Nicotine 1 binds at nicotinic acetylcholinergic receptors (nAChRs) but relatively little is known regarding its structure-affinity relationships at central receptors. The present study focuses on the pyridine 6-position of nicotine. Earlier studies from our laboratories suggested that the electronic (sigma) and/or lipophilic (pi) nature of the B-position substituent might influence nAChR affinity. To examine this in greater detail, we prepared and evaluated a series of 6-substituted nicotine analogs. The various analogs were found to bind at nAChRs with affinities (K-i values) ranging from 0.45 to > 10000 nM. It was demonstrated, for fifteen of these analogs, that affinity could not be explained on the basis of either sigma or pi. However, a combination of pi and Delta MOL VOL (representative of the volume of the 6-position substituent) accounted for affinity (r = 0.970, n = 15). The basicity of the pyridine nitrogen atom was also examined by determining the pK(a) values of several representative analogs. Consistent with the above studies examining sigma, as well as with previously published studies on peripheral nAChR binding, pK(a) alone did not account for variation in affinity. It would appear that lipophilic substituents at the pyridine 6-position contribute to nAChR affinity of nicotine analogs, but that affinity is further modulated by the steric size of this substituent in that increased size results in decreased affinity. (C) Elsevier, Paris.