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Titolo:
Antiparkinsonian agent piribedil displays antagonist properties at native,rat, and cloned, human alpha(2)-adrenoceptors: Cellular and functional characterization
Autore:
Millan, MJ; Cussac, D; Milligan, G; Carr, C; Audinot, V; Gobert, A; Lejeune, F; Rivet, JM; Brocco, M; Duqueyroix, D; Nicolas, JP; Boutin, JA; Newman-Tancredi, A;
Indirizzi:
Ctr Rech Croissy, Inst Rech Servier, Dept Psychopharmacol, F-78290 Paris, France Ctr Rech Croissy Paris France F-78290 hopharmacol, F-78290 Paris, France Ctr Rech Croissy, Inst Rech Servier, Dept Mol & Cellular Pharmacol, F-78290 Paris, France Ctr Rech Croissy Paris France F-78290 r Pharmacol, F-78290 Paris, France Univ Glasgow, Div Biochem & Mol Biol, Inst Biomed & Life Sci, Glasgow, Lanark, Scotland Univ Glasgow Glasgow Lanark Scotland Life Sci, Glasgow, Lanark, Scotland
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 297, anno: 2001,
pagine: 876 - 887
SICI:
0022-3565(200106)297:3<876:AAPDAP>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
GAMMA-S BINDING; DOPA-INDUCED DYSKINESIAS; LOCUS-COERULEUS LESIONS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; ADRENERGIC-RECEPTORS; MONOAMINERGIC TRANSMISSION; INVERSE AGONISM; D-3 RECEPTORS; MPTP;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
55
Recensione:
Indirizzi per estratti:
Indirizzo: Millan, MJ Ctr Rech Croissy, Inst Rech Servier, Dept Psychopharmacol, 125 Chemin Ronde, F-78290 Paris, France Ctr Rech Croissy 125 Chemin Ronde Paris France F-78290 France
Citazione:
M.J. Millan et al., "Antiparkinsonian agent piribedil displays antagonist properties at native,rat, and cloned, human alpha(2)-adrenoceptors: Cellular and functional characterization", J PHARM EXP, 297(3), 2001, pp. 876-887

Abstract

Compared with cloned. human (h)D-2 receptors (pK(1) = 6.9), the antiparkinsonian agent piribedil showed comparable affinity for h(alpha 2A)- (7.1) and h(alpha 2C)- (7.2) adrenoceptors (ARs), whereas its affinity for h(alpha 2B)-ARs was less marked (6.5). At h(alpha 2A)- and h(alpha 2C)-ARs, piribedil antagonized induction of [S-35]guanosine-5'-O-(3-thio)triphosphate (GTP gammaS) binding by norepinephrine (NE) with pK(b) values of 6.5 and 6.9, respectively. Furthermore, Schild analysis of the actions of piribedil at h(alpha 2A)-ARs indicated competitive antagonism, yielding a pA(2) of 6.5. At a porcine alpha (2A)-AR-Gi1 alpha -Cys351C (wild-type) fusion protein, piribedil competitively abolished (pA(2), = 6.5) GTPase activity induced by epinephrine. However, at a alpha (2A)-AR-Gi1 alpha -Cys3511 (mutant) fusion protein of amplified sensitivity, although still acting as a competitive antagonist (pA(2) = 6.2) of epinephrine, piribedil itself manifested weak partial agonist properties. Similarly, piribedil weakly induced mitogen-activated protein kinase phosphorylation via wild-type h(alpha 2A)-ARs, although attenuating its phosphorylation by NE. As demonstrated by functional [S-35]GTP gammaS autoradiography in rats, piribedil antagonized activation by NE ofalpha (2)-ARs in cortex, amygdala, and septum. Antagonist properties were also expressed in a dose-dependent enhancement of the firing rate of adrenergic neurons in locus ceruleus (0.125-4.0 mg/kg i.v.). Furthermore, piribedil (2.5-4.0 mg/kg s.c.) accelerated hippocampal NE synthesis, elevated dialysis levels of NE in hippocampus and frontal cortex, and blocked hypnotic-sedative properties of the alpha (2)-AR agonist xylazine. Finally, piribedilshowed only modest affinity for rat alpha (1)-ARs (5.9) and weakly antagonized NE-induced activation of phospholipase C via h(alpha 1A)-ARs (pK(b) = 5.6). In conclusion, piribedil displays essentially antagonist properties at cloned, human and cerebral, rat alpha (2)-ARs. Blockade of alpha (2)-ARs may, thus, contribute to its clinical antiparkinsonian profile.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/12/20 alle ore 01:15:51