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Titolo:
A-85380 [3-(2(S)-AZETIDINYLMETHOXY)PYRIDINE] - IN-VITRO PHARMACOLOGICAL PROPERTIES OF A NOVEL, HIGH-AFFINITY ALPHA-4-BETA-2 NICOTINIC ACETYLCHOLINE-RECEPTOR LIGAND
Autore:
SULLIVAN JP; DONNELLYROBERTS D; BRIGGS CA; ANDERSON DJ; GOPALAKRISHNAN M; PIATTONIKAPLAN M; CAMPBELL JE; MCKENNA DG; MOLINARI E; HETTINGER AM; GARVEY DS; WASICAK JT; HOLLADAY MW; WILLIAMS M; ARNERIC SP;
Indirizzi:
ABBOTT LABS,DIV PHARMACEUT PROD,NEUROSCI D47W,NEUROSCI DISCOVERY,BLDGAP10 ABBOTT PK IL 60064
Titolo Testata:
Neuropharmacology
fascicolo: 6, volume: 35, anno: 1996,
pagine: 725 - 734
SICI:
0028-3908(1996)35:6<725:A[-IP>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT-BRAIN; ALPHA-BUNGAROTOXIN; BINDING-SITES; FUNCTIONAL DIVERSITY; SUBTYPES; CELLS; EPIBATIDINE; RESPONSES; SUBUNITS; AGONIST;
Keywords:
ACH ACETYLCHOLINE; ALPHA-BGT ALPHA-BUNGAROTOXIN; DH-BETA-E DIHYDRO-BETA-ERYTHROIDINE; MLA METHYLLYCACONITINE; NACHR NICOTINIC ACETYLCHOLINE RECEPTOR;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
41
Recensione:
Indirizzi per estratti:
Citazione:
J.P. Sullivan et al., "A-85380 [3-(2(S)-AZETIDINYLMETHOXY)PYRIDINE] - IN-VITRO PHARMACOLOGICAL PROPERTIES OF A NOVEL, HIGH-AFFINITY ALPHA-4-BETA-2 NICOTINIC ACETYLCHOLINE-RECEPTOR LIGAND", Neuropharmacology, 35(6), 1996, pp. 725-734

Abstract

The in vitro pharmacological properties of a novel cholinergic channel ligand, A-85380 [3-(2(S)-azetidinylmethoxy)pyridine], were examined using tissue preparations that express different putative nAChR subtypes. In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human alpha 4 beta 2 nAChR subtype (K-i = 0.05 +/- 0.01 nM) relative to the human alpha 7 (K-i = 148 +/- 13 nM) and the muscle alpha 1 beta 1dg subtype expressed in Torpedo electroplax (K-i = 314 +/- 12 nM). The R-enantiomer of A-85380, A-159470, displays little enantioselectivity towards the alpha 4 beta 2 and alpha 1 beta 1 delta gamma subtypes but does display 12-fold enantioselectivity towards the alpha 7 subtype (K-i = 1275 +/- 199 nM). (+)- and (-)-Epibatidine display similar potencies at the human human alpha 4 beta 2 (K-i = 0.04 +/- 0.02 nM and 0.07 +/- 0.02 nM, respectively), human alpha7 (K-i = 16 +/- 2 nM and 22 +/- 3 nM, respectively) and muscle alpha 1 beta 1 delta g (K-i = 2.5 +/- 0.9 nM and 5.7 +/- 1.0 nM, respectively) nAChRs. Functionally, A-85380 is a potent activator of cation efflux through the human alpha 4 beta 2 (EC(50) = 0.7 +/- 0.1 mu M) and ganglionic (EC(50) = 0.8 +/- 0.04 mu M) subtypes,effects that are attenuated by pretreatment with mecamylamine (10 mu M). Further, A-85380 can activate (EC(50) = 8.9 +/- 1.9 mu M) currents through channels formed by injection of the human alpha 7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the alpha 7 nAChR antagonist, methyllycaconitine (10 nM). In all cases, A-85380 is more potent than (-)-nicotine but less potent than (+/-)-epibatidine. In neurotransmitter release studies, A-85380 stimulates the release of dopamine withan EC(50) value of 0.003 +/- 0.001 mu M which is equipotent to (+/-)-epibatidine, and 20-fold more potent that (-)-nicotine (EC(50) = 0.04 /- 0.009 mu M). Thus, A-85380 displays a profile of robust activationof a number of nAChR subtypes with substantially less affinity for [I-125]alpha-BgT sites than [H-3](-)-cytisine sites, suggesting that it may serve as a more selective pharmacologic probe for the alpha 4 beta2 subtype relative to the alpha 7 and alpha 1 beta 1 delta g nAChRs than (+/-)-epibatidine. Copyright (C) 1996 Elsevier Science Ltd.

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Documento generato il 05/07/20 alle ore 08:51:21