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). Previous attempts to determine whether lobeline fits the currently accepted nicotinic pharmacophore model have led to suggestions that the carbonyl function, rather than the hydroxyl group, is a major contributor to binding. Interestingly, however, it has never been empirically demonstrated that either oxygen function is actually required for interaction with the receptor. In the 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 reduction of the carbonyl group (to afford lobelanidine) also resulted in decreased 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; that is, replacement of the (-)lobeline hydroxyl group with a chloro group had no effect on affinity. Another finding of the present investigation is that removal of either one or both oxygen functions of lobeline results in compounds that retain the analgesic activity and potency of (-)lobeline, indicating that there is no direct relationship between neuronal nicotinic cholinergic (primarily alpha(4)beta(2) type) receptor affinity and spinal analgesia as measured in the tail-flick assay.
Flammia
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D
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
Dukat
M
M
Damaj
M I
MI
Martin
B
B
Glennon
R A
RA
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D008120:Lobeline / Q000031:analogs & derivatives* / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000700:Analgesics; D010880:Piperidines; D011978:Receptors, Nicotinic; D008120:Lobeline