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Kirstie A Bennett, Christopher J Langmead, Alan Wise, Graeme Milligan
Some growth hormone secretagogues act as agonists at the ghrelin receptor and have been described as "ago-allosteric" ligands because of an ability to also modulate the maximum efficacy and potency of ghrelin (Holst et al., 2005). In membranes prepared from cells coexpressing the human ghrelin receptor and the G protein Galpha(o1), N-[1(R)-1, 2-dihydro-1-ethanesulfonylspiro-3H-indole-3,4'-piperidin)-1'-yl]carbonyl-2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide (MK-677), growth hormone-releasing peptide 6 (GHRP-6), and the 2(R)-hydroxypropyl derivative of 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5-yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamide (L-692,585) each functioned as direct agonists, and each displayed higher efficacy than ghrelin...
October 2009: Molecular Pharmacology
J J Sevigny, J M Ryan, C H van Dyck, Y Peng, C R Lines, M L Nessly
BACKGROUND: In animals, insulin-like growth factor-1 (IGF-1) increases clearance of beta-amyloid, a pathologic hallmark of Alzheimer disease (AD), from the CNS. Serum IGF-1 level decreases with age, and shows a further decrease in AD. We examined whether the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, slows the rate of progression of symptoms in patients with AD. METHODS: A double-blind, multicenter study was conducted in which 563 patients with mild to moderate AD were randomized to receive MK-677 25 mg or placebo daily for 12 months...
November 18, 2008: Neurology
Ralf Nass, Suzan S Pezzoli, Mary Clancy Oliveri, James T Patrie, Frank E Harrell, Jody L Clasey, Steven B Heymsfield, Mark A Bach, Mary Lee Vance, Michael O Thorner
BACKGROUND: Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated. OBJECTIVE: To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults...
November 4, 2008: Annals of Internal Medicine
Birgitte Holst, Thomas M Frimurer, Jacek Mokrosinski, Tine Halkjaer, Karina B Cullberg, Christina R Underwood, Thue W Schwartz
A library of robust ghrelin receptor mutants with single substitutions at 22 positions in the main ligand-binding pocket was employed to map binding sites for six different agonists: two peptides (the 28-amino-acid octanoylated endogenous ligand ghrelin and the hexapeptide growth hormone secretagogue GHRP-6) plus four nonpeptide agonists-the original benzolactam L-692,429 [3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5-yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamide], the spiroindoline sulfonamide MK-677 [N-[1(R)-1, 2-dihydro-1-ethanesulfonylspiro-3H-indole-3,4'-piperidin)-1'-yl]carbonyl-2-(phenylmethoxy)-ethyl-2-amino-2-methylpropanamide], and two novel oxindole derivatives, SM-130686 [(+)-6-carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole] and SM-157740 [(+/-)-6-carbamoyl-3-(2, 4-dichlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole)]...
January 2009: Molecular Pharmacology
Gareth Arnott, Heloise Brice, Jonathan Clayden, Emma Blaney
Treatment of N-arylisonicotinamides with trifluoromethanesulfonic anhydride triggers intramolecular nucleophilic attack of the aryl ring on the 4-position of the pyridinium intermediate. The products are spirocyclic dihydropyridines which can be converted to valuable spirocyclic piperidines related to biologically active molecules such as MK-677.
July 17, 2008: Organic Letters
Birgitte Holst, Erik Brandt, Anders Bach, Anders Heding, Thue W Schwartz
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...
September 2005: Molecular Endocrinology
J Svensson, C L Boguszewski, F Shibata, B Carlsson, L M S Carlsson, B-A Bengtsson
Growth hormone (GH) consists of several isoforms. We have studied the proportion, expressed as percentage of total GH concentration, of non-22kDa (non-22K) GH isoforms and 20K GH during 8-week oral treatment with MK-677 25mg daily in 12 obese males. The proportion of non-22K GH isoforms in peak total GH samples after the initial MK-677 administration was higher than that after 2 and 8 weeks (p<0.01 and p<0.05, respectively). In selected non-peak total GH samples after the initial MK-677 administration, however, the proportion of non-22K GH isoforms was similar to that in the peak total GH samples after 2 and 8 weeks...
February 2003: Growth Hormone & IGF Research
T Tokunaga, W E Hume, T Umezome, K Okazaki, Y Ueki, K Kumagai, S Hourai, J Nagamine, H Seki, M Taiji, H Noguchi, R Nagata
A series of substituted oxindole derivatives was synthesized and evaluated for growth hormone (GH) releasing activity using cultured rat pituitary cells. (+)-6-Carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity (EC(50) = 3.0 nM), while the other enantiomer 37R had reduced activity. The absolute configuration of 37S was confirmed by X-ray crystallographic analysis. Compound 37S showed a good pharmacokinetic profile in rats with 28% oral bioavailability at 10 mg/kg and excellent in vivo activity as evidenced by a significant weight gain after 4 days of oral administration at 10 mg/kg twice a day...
December 20, 2001: Journal of Medicinal Chemistry
J Nagamine, R Nagata, H Seki, N Nomura-Akimaru, Y Ueki, K Kumagai, M Taiji, H Noguchi
SM-130686, an oxindole derivative, is a novel orally active GH secretagogue (GHS) which is structurally distinct from previously reported GHSs such as MK-677, NN703 and hexarelin. SM-130686 stimulates GH release from cultured rat pituitary cells in a dose-dependent manner. Half-maximum stimulation was observed at a concentration of 6.3+/-3.4 nM. SM-130686-induced GH release was inhibited by a GHS antagonist, but not by a GH-releasing hormone antagonist. SM-130686 dose-dependently inhibited the binding of radiolabeled ligand, (35)S-MK-677, to human GHS receptor 1a (IC(50)=1...
December 2001: Journal of Endocrinology
I Bedendi, M P Gallo, D Malan, R C Levi, G Alloatti
The synthetic growth hormone (GH) secretagogue hexarelin has important cardiac effects, that include a reduction of dysfunction in ischemic-reperfused hearts from GH-deficient rats after a chronic treatment and an increase of ejection fraction in acutely treated men. To investigate the mechanisms of its cardiac activity, we studied the effects of hexarelin (1-10 microM) on contractility of rat papillary muscles. We observed, in hexarelin treated papillary muscles, an improved recovery of contractility after anoxia...
September 21, 2001: Life Sciences
M G Murphy, S Weiss, M McClung, T Schnitzer, K Cerchio, J Connor, D Krupa, B J Gertz
GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months...
March 2001: Journal of Clinical Endocrinology and Metabolism
J Svensson, S Lall, S L Dickson, B A Bengtsson, J Rømer, I Ahnfelt-Rønne, C Ohlsson, J O Jansson
Growth hormone (GH) is of importance for normal bone remodelling. A recent clinical study demonstrated that MK-677, a member of a class of GH secretagogues (GHSs), increases serum concentrations of biochemical markers of bone formation and bone resorption. The aim of the present study was to investigate whether the GHSs, ipamorelin (IPA) and GH-releasing peptide-6 (GHRP-6), increase bone mineral content (BMC) in young adult female rats. Thirteen-week-old female Sprague-Dawley rats were given IPA (0.5 mg/kg per day; n=7), GHRP-6 (0...
June 2000: Journal of Endocrinology
G Muccioli, F Broglio, M R Valetto, C Ghè, F Catapano, A Graziani, M Papotti, G Bisi, R Deghenghi, E Ghigo
Growth Hormone (GH)-releasing peptides (GHRPs) and their non peptidyl analogues are synthetic molecules which exhibit strong, dosedependent and reproducible GH-releasing activity but also significant PRL- and ACTH/cortisol-releasing effects. An influence of these compounds on food intake and sleep pattern has been also shown. The neuroendocrine activities of GHRPs are mediated by specific receptors subtypes that have been identified in the pituitary gland, hypothalamus and various extra-hypothalamic brain regions with (125)I-Tyr-Ala-hexarelin, an octapeptide of the GHRP family...
February 2000: Annales D'endocrinologie
J H Kennedy, J L Bowers, J A Dodge, C W Lugar, T A Shepherd, V S Sharp
Chromatographic separations of new growth hormone secretagogue compounds were developed to support structure-activity relationship (SAR) studies in conjunction with lead optimization. These new compounds differed from Merck's MK-677 by having two chiral centers and thus diastereomeric mixtures were generated. Separation of initial compounds in the SAR was achieved on a Kromasil C18 column using an ammonium acetate buffer and acetonitrile. However, additional candidates were not separable on C18 columns and a chiral Kromasil CHI-DMB column was used to resolve the diastereomeric compounds...
March 3, 2000: Journal of Chromatography. A
J Svensson, B Carlsson, L M Carlsson, J O Jansson, B A Bengtsson
OBJECTIVE: Growth hormone (GH) treatment decreases total body fat while this effect has not yet been documented for the oral GH secretagogue MK-677. In the present study, the effects of MK-677 treatment on serum levels of leptin, thyroid hormones and testosterone were determined. DESIGN: This was a randomized, double-blind, and parallel study. Twenty-four healthy obese males, 19-49 years of age, with body mass index (BMI) > 30 kg/m2 and a waist:hip ratio > 0...
April 1999: Clinical Endocrinology
M G Murphy, M A Bach, D Plotkin, J Bolognese, J Ng, D Krupa, K Cerchio, B J Gertz
Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either circulating or locally produced insulin-like growth factor I (IGF-I). We determined the effect of chronic administration of the GH secretagogue, MK-677, on serum IGF-I and markers of bone turnover in 187 elderly adults (65 years or older) enrolled in three randomized, double-blind, placebo-controlled clinical studies lasting 2-9 weeks...
July 1999: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
J Svensson, J O Jansson, M Ottosson, G Johannsson, M R Taskinen, O Wiklund, B A Bengtsson
Obesity is associated with blunted GH secretion and an unfavorable lipoprotein pattern. The objective of this study was to investigate the effects of treatment with the oral GH secretagogue MK-677 on lipoproteins in otherwise healthy obese males. The study was randomized, double blind, and parallel. Twenty-four obese males, aged 18-50 yr, with body mass index greater than 30 kg/m2 and waist/hip ratio above 0.95 were treated with 25 mg MK-677 (n = 12) or placebo (n = 12) daily for 8 weeks. MK-677 treatment did not significantly change serum lipoprotein(a) [Lp(a)] levels...
June 1999: Journal of Clinical Endocrinology and Metabolism
E Ghigo, E Arvat, F Camanni
Growth hormone secretagogues (GHS) are synthetic, non-natural peptidyl and nonpeptidyl molecules with potent stimulatory effect on somatotrope secretion. They have no structural homology with growth hormone-releasing hormone (GHRH) and act via a specific receptor, which has now been cloned and is present at both the pituitary and hypothalamic level. This evidence strongly suggests the existence of a still unknown natural GHS-like ligand. Several data favour the hypothesis that GHS could counteract somatostatinergic activity at both the pituitary and hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism...
April 1998: Annals of Medicine
J Svensson, C Ohlsson, J O Jansson, G Murphy, D Wyss, D Krupa, K Cerchio, W Polvino, B Gertz, D Baylink, S Mohan, B A Bengtsson
The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK-677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double-blind, parallel, placebo-controlled study. Twenty-four healthy obese males, 19-49 years of age, with body mass index > 30 kg/m2 were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK-677 increased markers of bone formation; a 23% increase in the carboxy-terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK-677 treatment (p < 0...
July 1998: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
J Svensson, L Lönn, J O Jansson, G Murphy, D Wyss, D Krupa, K Cerchio, W Polvino, B Gertz, I Boseaus, L Sjöström, B A Bengtsson
Obesity is associated with blunted GH secretion, unfavorable body composition, and increased cardiovascular mortality. The objective of this study was to investigate the effects of oral treatment with the GH secretagogue MK-677 on GH secretion and body composition in otherwise healthy obese males. The study was randomized, double blind, parallel, and placebo controlled. Twenty-four obese males, aged 18-50 yr, with body mass indexes greater than 30 kg/m2 and waist/hip ratios greater than 0.95, were treated with MK-677 25 mg (n = 12) or placebo (n = 12) daily for 8 weeks...
February 1998: Journal of Clinical Endocrinology and Metabolism
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