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Titolo:
Lobeline: Structure-affinity investigation of nicotinic acetylcholinergic receptor binding
Autore:
Flammia, D; Dukat, M; Damaj, MI; Martin, B; Glennon, RA;
Indirizzi:
Virginia Commonwealth Univ, Med Coll Virginia, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA Virginia Commonwealth Univ Richmond VA USA 23298 , Richmond, VA 23298 USA Virginia Commonwealth Univ, Med Coll Virginia, Sch Med, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA Virginia Commonwealth Univ Richmond VA USA 23298 , Richmond, VA 23298 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 18, volume: 42, anno: 1999,
pagine: 3726 - 3731
SICI:
0022-2623(19990909)42:18<3726:LSIONA>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
AGONISTS; RELEASE; MICE; HYDROCHLORIDE; (-)-LOBELINE; (-)-NICOTINE; PHARMACOLOGY; RESPONSES; STIMULANT; DOPAMINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Glennon, RA Virginia Commonwealth Univ, Med Coll Virginia, Sch Pharm, DeptMed Chem, Richmond, VA 23298 USA Virginia Commonwealth Univ Richmond VA USA 23298 VA 23298 USA
Citazione:
D. Flammia et al., "Lobeline: Structure-affinity investigation of nicotinic acetylcholinergic receptor binding", J MED CHEM, 42(18), 1999, pp. 3726-3731

Abstract

(-)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 oxygenfunctions 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/09/20 alle ore 16:09:16