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

Nicotine 1 binds at nicotinic acetylcholinergic receptors (nAChRs) but rela tively little is known regarding its structure-affinity relationships at ce ntral receptors. The present study focuses on the pyridine 6-position of ni cotine. 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 an d evaluated a series of 6-substituted nicotine analogs. The various analogs were found to bind at nAChRs with affinities (K-i values) ranging from 0.4 5 to > 10000 nM. It was demonstrated, for fifteen of these analogs, that af finity 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 bas icity of the pyridine nitrogen atom was also examined by determining the pK (a) values of several representative analogs. Consistent with the above stu dies examining sigma, as well as with previously published studies on perip heral nAChR binding, pK(a) alone did not account for variation in affinity. It would appear that lipophilic substituents at the pyridine 6-position co ntribute to nAChR affinity of nicotine analogs, but that affinity is furthe r modulated by the steric size of this substituent in that increased size r esults in decreased affinity. (C) Elsevier, Paris.