Lobeline: Structure-affinity investigation of nicotinic acetylcholinergic receptor binding

(-)Lobeline (1) and (-)nicotine (2) bind at neuronal nicotinic cholinergic (nACh) receptors with high affinity (K-i = 4 and 2 nM, respectively). Previ ous attempts to determine whether lobeline fits the currently accepted nico tinic pharmacophore model have led to suggestions that the carbonyl functio n, rather than the hydroxyl group, is a major contributor to binding. Inter estingly, however, it has never been empirically demonstrated that either o xygen function is actually required for interaction with the receptor. In t he present investigation we systematically examined a number of abbreviated analogues of lobeline and found that removal of either one or both oxygen functions reduces the affinity of lobeline by at least 25-fold; furthermore , oxidation of the (-)lobeline hydroxyl group (to afford lobelanine) or red uction of the carbonyl group (to afford lobelanidine) also resulted in decr eased affinity. Although it is likely that both oxygen functions contribute to the high affinity of(-)lobeline at nACh receptors, it is concluded that the presence of both oxygen functions is not a requirement for binding; th at is, replacement of the (-)lobeline hydroxyl group with a chloro group ha d no effect on affinity. Another finding of the present investigation is th at removal of either one or both oxygen functions of lobeline results in co mpounds that retain the analgesic activity and potency of (-)lobeline, indi cating that there is no direct relationship between neuronal nicotinic chol inergic (primarily alpha(4)beta(2) type) receptor affinity and spinal analg esia as measured in the tail-flick assay.