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Titolo:
DISCOVERY OF A NOVEL SUPERPOTENT AND SELECTIVE MELANOCORTIN-4 RECEPTOR ANTAGONIST (HS024) - EVALUATION IN-VITRO AND IN-VIVO
Autore:
KASK A; MUTULIS F; MUCENIECE R; PAHKLA R; MUTULE I; WIKBERG JES; RAGO L; SCHIOTH HB;
Indirizzi:
UPPSALA UNIV,DEPT PHARMACEUT PHARMACOL,CTR BIOMED,BOX 591 S-75124 UPPSALA SWEDEN UPPSALA UNIV,DEPT PHARMACEUT PHARMACOL,CTR BIOMED S-75124 UPPSALA SWEDEN TARTU STATE UNIV,DEPT PHARMACOL EE-50090 TARTU ESTONIA INST ORGAN SYNTH,PHARMACOL LAB LV-1006 RIGA LATVIA
Titolo Testata:
Endocrinology
fascicolo: 12, volume: 139, anno: 1998,
pagine: 5006 - 5014
SICI:
0013-7227(1998)139:12<5006:DOANSA>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
CORTICOTROPIN-RELEASING FACTOR; ALPHA-MELANOTROPIN; MOLECULAR-CLONING; BEHAVIORAL-RESPONSES; RADIOLIGAND BINDING; BIOLOGICAL-ACTIVITY; HORMONE; ANALOGS; RATS; MSH;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
49
Recensione:
Indirizzi per estratti:
Citazione:
A. Kask et al., "DISCOVERY OF A NOVEL SUPERPOTENT AND SELECTIVE MELANOCORTIN-4 RECEPTOR ANTAGONIST (HS024) - EVALUATION IN-VITRO AND IN-VIVO", Endocrinology, 139(12), 1998, pp. 5006-5014

Abstract

Several novel cyclic MSH analogs were synthesized, and their binding properties were tested on cells transiently expressing the human melanocortin-1 (MC1), MC3, MC4, and MC5 receptors. We discovered a novel substance (HS024) that showed about 20-fold selectivity and very high affinity (K-i = 0.29 nM) for the MC4 receptor. HS024 (cyclic [AcCys(3),Nle(4),Arg(5),D-Nal(7),Cys-NH211] alpha-MSH-(3-11)) has a 29-membered atom ring structure that includes an Arg in position 5. HS024 was foundto antagonize an alpha MSH-induced cAMP response in cells expressing the human MC1, MC3, MC4, and MC5 receptor DNAs. HS024 also caused a dose-dependent increase in food intake, with a maximum response (4-fold increase) at a l-nmol dose injected intracerebroventricularly in free feeding rats. We also tested SHU9119, a previously described nonselective MC receptor antagonist, and found HS024 and SHU9119 to have similar potencies for increasing food intake, although SHU9119 appeared to induce more serious side-Effects. HS024 increased the food intake of free feeding rats to levels comparable to those in food-deprived rats, indicating that blockade of the MC4 receptor is a highly effective way to increase feeding. Moreover, we tested the effects of intracerebroventricular injections of HS024 in elevated plus-maze and open-field experiments on rats. In these tests, HS024 did not appear to affect emotionality or locomotor activity, suggesting that the MC4 receptor does not mediate the anxiogenic-like and locomotor effects related to the melanocortic peptides.

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Documento generato il 15/07/20 alle ore 14:16:25