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Titolo:
INTERACTION OF THE ANXIOGENIC AGENT, RS-30199, WITH 5-HT1A RECEPTORS - MODULATION OF SEXUAL-ACTIVITY IN THE MALE-RAT
Autore:
SPEDDING M; NEWMANTANCREDI A; MILLAN MJ; DACQUET C; MICHEL AN; JACOBY E; VICKERY B; TALLENTIRE D;
Indirizzi:
INST RECH INT SERVIER,192 AVE CHARLES DE GAULLE F-92200 NEUILLY SUR SEINE FRANCE CROISSY RES CTR,SERVIER,INST INT F-78290 PARIS FRANCE ROCHE BIOSCI PALO ALTO CA 94304
Titolo Testata:
Neuropharmacology
fascicolo: 6, volume: 37, anno: 1998,
pagine: 769 - 780
SICI:
0028-3908(1998)37:6<769:IOTAAR>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-COUPLED RECEPTORS; SITE-DIRECTED MUTAGENESIS; ALPHA-2-ADRENOCEPTOR ANTAGONIST; NORADRENERGIC FUNCTION; PANIC DISORDER; BINDING-SITES; 7TM RECEPTORS; YOHIMBINE; AGONIST; BEHAVIOR;
Keywords:
5-HT1A RECEPTOR; RS-30199; DELEQUAMINE; SEXUAL BEHAVIOR; ANXIETY; BUSPIRONE; RECEPTOR-LIGAND INTERACTION; DRUG DESIGN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
79
Recensione:
Indirizzi per estratti:
Citazione:
M. Spedding et al., "INTERACTION OF THE ANXIOGENIC AGENT, RS-30199, WITH 5-HT1A RECEPTORS - MODULATION OF SEXUAL-ACTIVITY IN THE MALE-RAT", Neuropharmacology, 37(6), 1998, pp. 769-780

Abstract

RS-30199 has been shown previously to have atypical interactions at 5-HT1A receptors. RS-30199 and RS-64459, an analogue of buspirone with a buspirone side chain: were compared with the classic, partial agonist at 5-HT1A receptors, 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) and buspirone. At human (h) 5-HT1A receptors in CHO cells. RS-30199-193 (racemate) and its enantiomers (-197, -198) inhibited [H-3]-8-OH-DPAT binding (RS-30199-198, k(i), 29.7 +/- 11.7 nM; RS-30199-197, k(i), 74.1 +/- 11.7 nM) as did RS-64459 (k(i), 24.9 +/- 6.0 nM), but RS-30199-197 and -198 were almost full agonists in a [S-35]-GTP gamma S binding assay, whereas RS-64459 was a partial agonist, resembling buspirone and 8-OH-DPAT. RS-64459 and the enantiomers of RS-30199 had weaker affinity for 5-HT2C and 5-HT7 receptors. These compounds did not induce the 5-HT behavioural syndrome in male rats. However, in a model where naive male rats were introduced to estrogen-progesterone primed, sexually receptive female rats, RS-30199-197 (0.1, 1, 10 mg/kg, s.c.) had a profound inhibitory effect on sexual behaviour score. Neither buspirone nor 8-OH-DPAT reduced the sexual behaviour score. Unlike 8-OH-DPAT, which shortens intromission latency, RS-30199 prolonged intromission latency. RS-30199 (10 mg/kg s.c.) fully inhibited the facilitationof sexual behaviour caused by the alpha(2)-adrenoceptor antagonist, delequamine (0.1 mg/kg, p.o.). In contrast, RS-64459 (100, 250, 1000 and 4000 mu g/kg, s.c.) failed to modify the sexual behaviour score and did not modify intromission latency. The differences between the effects of RS-30199 and RS-64459 in binding and functional experiments are supported by molecular models of the receptor-ligand interaction, where the compounds interact in different ways with the receptor; a model is proposed for the allosteric interaction of different agents with the receptor, resulting in different functional profiles. RS-30199 can be considered an atypical agonist at 5-HT1A receptors. (C) 1998 Elsevier Science Ltd. All rights reserved.

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Documento generato il 03/04/20 alle ore 08:03:19