european research peptides

Ibutamoren MK-677

Ibutamoren MK-677
Ibutamoren MK-677
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Molecular formula: C27H36N4O5S.CH4O3S

Molecular weight624.776

Synonyms: Ibutamoren mesylate; MK-677; 2-Amino-N-[(1R)-2-[1,2-dihydro-1-(methylsulfonyl)spiro[3H-indole-3,4'-piperidin]-1'-yl]-2-oxo-1-[(phenylmethoxy)methyl]ethyl]-2-methylpropanamide methanesulfonate; (R)-1'-(2-Methylalanyl-O-benzyl-D-seryl)-1-(Methylsulfonyl)-1,2-dihydrospiro[indole-3,4'-piperidine] Mesylate; Crescendo; IbutaMoren Mesylate (MK-677); MK-667; N-[1(R)-1,2-Dihydro-1-methanesulfonylspiro-3H-indole-3,4′-piperidin)-1′-yl]carbonyl-2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide methanesulfonate; IBUTAMORIN

Biological half-life: 4-6 hours

 

Ibutamoren mesylate MK-677

Ibutamoren (INN) (developmental code names MK-677, MK-0677, L-163,191) is a non-peptidic, potent, long-acting, orally-active, and selective agonist of the ghrelin receptor and a growth hormone secretagogue, mimicking the growth hormone (GH)-stimulating action of the endogenous hormone ghrelin. It has been demonstrated to increase the release of, and produces sustained increases in plasma levels of several hormones including GH and insulin-like growth factor 1 (IGF-1), but without affecting cortisol levels. It is currently under development as a potential treatment for reduced levels of these hormones, such as in children or elderly adults with growth hormone deficiency, and human studies have shown it to increase both muscle mass and bone mineral density, making it a promising therapy for the treatment of frailty in the elderly. It also alters metabolism of body fat and so may have application in the treatment of obesity.

 

Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist

Two nonpeptide (L692,429 and MK-677) and two peptide [GH-releasing peptide (GHRP)-6 and ghrelin] agonists were compared in binding and in signal transduction assays: calcium mobilization, inositol phosphate turnover, cAMP-responsive element (CRE), and serum-responsive element (SRE) controlled transcription, as well as arrestin mobilization. MK-677 acted as a simple agonist having an affinity of 6.5 nm and activated all signal transduction systems with similar high potency (0.2-1.4 nm). L-692,429 also displayed a very similar potency in all signaling assays (25-60 nm) but competed with a 1000-fold lower apparent affinity for ghrelin binding and surprisingly acted as a positive allosteric receptor modulator by increasing ghrelin's potency 4- to 10-fold. In contrast, the potency of GHRP-6 varied 600-fold (0.1-61 nm) depending on the signal transduction assay, and it acted as a negative allosteric modulator of ghrelin signaling. Unexpectedly, the maximal signaling efficacy for ghrelin was increased above what was observed with the hormone itself during coadministration with the nonendogenous agonists. It is concluded that agonists for the ghrelin receptor vary both in respect of their intrinsic agonist properties and in their ability to modulate ghrelin signaling. A receptor model is presented wherein ghrelin normally only activates one receptor subunit in a dimer and where the smaller nonendogenous agonists bind in the other subunit to act both as coagonists and as either neutral (MK-677), positive (L-692,429), or negative (GHRP-6) modulators of ghrelin function. It is suggested that an optimal drug candidate could be an agonist that also is a positive modulator of ghrelin signaling.