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Titolo:
S18616, a highly potent, spiroimidazoline agonist at alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine
Autore:
Millan, MJ; Dekeyne, A; Newman-Tancredi, A; Cussac, D; Audinot, V; Milligan, G; Duqueyroix, D; Girardon, S; Mullot, J; Boutin, JA; Nicolas, JP; Renouard-Try, A; Lacoste, JM; Cordi, A;
Indirizzi:
Inst Rech Servier, Ctr Rech Croissy, Dept Psychopharmacol, F-78290 Paris, France Inst Rech Servier Paris France F-78290 opharmacol, F-78290 Paris, France Inst Rech Servier, Ctr Rech Croissy, Dept Mol & Cellular Pharmacol, F-78290 Paris, France Inst Rech Servier Paris France F-78290 Pharmacol, F-78290 Paris, France Inst Rech Servier, Ctr Rech Suresnes, Chem Dept C, Paris, France Inst RechServier Paris France ech Suresnes, Chem Dept C, Paris, France Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Glasgow, Lanark, Scotland Univ Glasgow Glasgow Lanark Scotland Mol Biol, Glasgow, Lanark, Scotland
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 295, anno: 2000,
pagine: 1192 - 1205
SICI:
0022-3565(200012)295:3<1192:SAHPSA>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
ADRENERGIC-RECEPTORS; RAT R(ALPHA-2A); DORSAL HORN; SUBTYPES; ANTAGONIST; RESPONSES; BINDING; MICE; IMMUNOREACTIVITY; ADRENOCEPTORS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Millan, MJ Inst Rech Servier, Ctr Rech Croissy, Dept Psychopharmacol, 125 Chemin Ronde, F-78290 Paris, France Inst Rech Servier 125 Chemin Ronde Paris France F-78290 France
Citazione:
M.J. Millan et al., "S18616, a highly potent, spiroimidazoline agonist at alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine", J PHARM EXP, 295(3), 2000, pp. 1192-1205

Abstract

S18616 {(S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(8'-chloro-1',2', 3', 4'-tetrahydronaphthalene)]} displayed high affinity at native rat alpha (2)-adrenoceptors (AR)s (pK(i), 9.8), native human (h) alpha (2A)-ARs (9.6), and cloned h alpha (2A)- (9.5), h alpha (2B) - (9.2), and h alpha (2C)- (9.0) ARs. It showed 40-fold lower affinity for h alpha (1A)-ARs (8.4) and greater than or equal to 100-fold lower affinity for rat alpha (1)-ARs (7.1), h alpha (1B)-ARs (7.7), h alpha (1D)-ARs (7.6), imidazoline(1) (7.4), and imidazoline(2) (7.4) sites and >100-fold lower affinity for all other(>50) sites. At h alpha (2A)-ARs, in guanosine-5'-O-(3-[S-35]thio) triphosphate binding studies, S18616 was a potent (partial) agonist: log effectiveconcentration (pEC(50)), 9.3/maximal effect, 51%. This observation was corroborated employing a h alpha (2A)-Gi1 alpha fusion protein/ GTPase assay (9.0/40%) in which the actions of S18616 were blocked by pertussis toxin. Employing guanosine-5'-O-(3[S-35] thio) triphosphate binding assays, S18616 was also a partial agonist at h alpha (2C)-ARs (8.2/63%) but a full agonist (8.4/124%) at h alpha (2B)-ARs. At h alpha (2A)-, h alpha (2B)-, and h alpha (2C)-ARs, the selective alpha (2)-AR antagonist, atipamezole, abolished the actions of S18616: pK(b) values of 9.1, 9.1, and 9.4, respectively. As determined by depletion of membrane-bound [H-3] phosphatidyl inositols, S18616 behaved as a (less potent) agonist (7.8/79%) at h alpha (1A)-ARs, an action abolished by prazosin (pK(b), 8.9). Reflecting alpha (2)-AR agonist properties, S18616 potently (greater than or equal to1 mug/kg, s.c.) and dose dependently elicited hypothermia and antinociception (nine diverse models) in rodents. These actions were dose dependently inhibited by chemically diverse alpha (2)- versus alpha (1)-AR antagonists, atipamezole, idazoxan, RX821,002, and BRL44418 (a preferential alpha (2A)-AR ligand). In contrast, the actions of S18616 were unaffected by the alpha (1)-AR antagonists, ARC239and prazosin (which preferentially block alpha (2B/2C)-versus alpha (2A)-ARs). Although the affinity of dexmedetomidine at alpha (2)-ARs was lower than S18616; it displayed a similar receptor and functional profile. Clonidine displayed lower efficacy than S18616, was substantially less potent, and had marked affinity for imidazoline(1) sites and alpha (1)-ARs. In conclusion, S18616 is a novel, selective, and highly potent agonist at alpha (2)-ARs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/09/20 alle ore 16:10:36