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Titolo:
PHARMACOLOGY OF NOVEL NICOTINIC ANALOGS
Autore:
DAMAJ MI; GLASSCO W; DUKAT M; MAY EL; GLENNON RA; MARTIN BR;
Indirizzi:
VIRGINIA COMMONWEALTH UNIV,MED COLL VIRGINIA,DEPT PHARMACOL & TOXICOL,BOX 980613 RICHMOND VA 23298 VIRGINIA COMMONWEALTH UNIV,MED COLL VIRGINIA,DEPT MED CHEM RICHMOND VA 23298
Titolo Testata:
Drug development research
fascicolo: 3-4, volume: 38, anno: 1996,
pagine: 177 - 187
SICI:
0272-4391(1996)38:3-4<177:PONNA>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
BINDING-SITES; ANATOXIN ANALOGS; EPIBATIDINE; RECEPTOR; AGONIST; BRAIN; ENANTIOMERS; LIGAND;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
27
Recensione:
Indirizzi per estratti:
Citazione:
M.I. Damaj et al., "PHARMACOLOGY OF NOVEL NICOTINIC ANALOGS", Drug development research, 38(3-4), 1996, pp. 177-187

Abstract

It is believed that nicotine exerts its psychoactive and addictive effects through neuronal nicotinic receptors (nAChRs). Surprisingly, fewsystematic structure-activity relationship (SAR) studies have been undertaken with nicotine. The major goal of our laboratory is to characterize the mechanisms by which nicotine produces some of its behavioraleffects, with the ultimate aim of developing novel nicotine receptor ligands. Nicotine analogs with a wide range of receptor affinities were synthesized and evaluated for their ability to reduce spontaneous activity, produce antinociception, and engender nicotine-like respondingin drug discrimination. Mecamylamine antagonism was then used to verify that these effects were mediated through the nicotinic receptor. Our results showed that an intact pyrrolidine ring, although not essential, appears to be optimal for nicotine activity and that bulky substituents dramatically attenuate receptor affinity. In addition, the ''pyrrolidine'' N in the up position is more important for activity than the down position. Epibatidine analogs revealed that halogen substitution at position 2 was not sufficient to account for all of epibatidine'spotency. Finally, correlation of receptor affinity with pharmacological potency suggested that nicotine-induced antinociception and hypomotility may involve the activation of nicotinic receptors containing an alpha(2) beta(2) subunit combination. These results clearly show that this strategy can be used to distinguish among nicotine analogs with different mechanisms of action and can serve as the basis for an evaluation model. (C) 1996 Wiley-Liss, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/09/20 alle ore 09:36:56