S38151 [p-guanidinobenzoyl-[Des-Gly10]-MCH(7-17)] is a potent and selective antagonist at the MCH1 receptor and has anti-feeding properties in vivo

Audinot, Valérie; Zuana, Odile Della; Fabry, Nelly; Ouvry, Christine; Nosjean, Olivier; Henlin, Jean‐Michel; Fauchère, Jean‐Luc; Boutin, Jean A.

doi:10.1016/j.peptides.2009.07.007

Cited by 9 publications

(13 citation statements)

References 39 publications

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“…However, the BBB-crossing antagonist used in this study also induced a modest conditioned taste aversion (Eric Hu et al 2008), which complicates interpretation of these results. Additional studies found that central MCH1R antagonist injection reduced MCH-induced food intake but failed to decrease spontaneous food intake when it was injected alone (Audinot et al 2009; Morens et al 2005). …”

Section: Introductionmentioning

confidence: 99%

Recent Updates on the Melanin-Concentrating Hormone (MCH) and Its Receptor System: Lessons from MCH1R Antagonists

et al. 2010

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Melanin-concentrating hormone (MCH) is a 19-amino-acid cyclic peptide which was originally found to lighten skin color in fish that is highly conserved among many species. MCH interacts with two G-protein-coupled receptors, MCH1R and MCH2R, but only MCH1R is expressed in rodents. MCH is mainly synthesized in the lateral hypothalamus and zona incerta, while MCH1R is widely expressed throughout the brain. Thus, MCH signaling is implicated in the regulation of many physiological functions. The identification of MCH1R has led to the development of small-molecule MCH1R antagonists that can block MCH signaling. MCH1R antagonists are useful not only for their potential therapeutic value, but also for understanding the physiological functions of the endogenous MCH system. Here, we review the physiological functions of the MCH system which have been investigated using MCH1R antagonists such as food intake, anxiety, depression, reward, and sleep. This will help us understand the physiological functions of the MCH system and suggest some of the potential applications of MCH1R antagonists in human disorders.

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Section: Introductionmentioning

confidence: 99%

Recent Updates on the Melanin-Concentrating Hormone (MCH) and Its Receptor System: Lessons from MCH1R Antagonists

et al. 2010

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“…This pseudopeptide is derived from another, very similar agonist, pGua (MCH7-17) (Audinot et al, 2001a, 2009). In Chinese hamster ovary cells over-expressing MCH 1 , S38151 exhibited a K i of 80 nM in a [ 125 I]-S36057 binding assay and was a potent and full antagonist ( KB = 4.3 nM in a GTPγS binding assay, and KB = 210 nM in a calcium flux assay) (Audinot et al, 2009). This activity was specific to MCH 1 , since it has no activity with respect to MCHR2 at concentrations of less than 10 μM.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we have investigated the effects of a selective MCH 1 peptide antagonist, S38151 (Audinot et al, 2001a, 2009), on food intake, drinking, body weight, and/or motility in lean rats and mice, as well as in Zucker fa/fa rats, ob/ob mice, and DIO mice. Central acute administration of S38151 inhibited proMCH131-165 (MCH-NEI peptide)-induced feeding in lean animals in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…MCH and S38151 (Audinot et al, 2009) were obtained from Polypeptide Laboratories (Illkirch, France) and/or from Genepep (Saint Jean de Védas, France). They were of purity exceeding 97%.…”

Section: Methodsmentioning

confidence: 99%

“…In agreement with our initial search for better agonists (Audinot et al, 2001a,b), we explored the possibility of designing natural peptides or pseudopeptides [pseudopeptides are peptides including one or more exotic aminoacid(s) in their sequence] with good MCH 1 antagonism and fair in vivo stability. We succeeded in describing S38151 (Audinot et al, 2009), a potent peptide at MCH 1 with antagonistic activity in the nanomolar range. The aim of the present study was to evaluate the possible inhibition of S38151 on food and water intakes, body weight, and motility after one-time or repeated daily peripheral administration in different rodent models of obesity.…”

Section: Introductionmentioning

confidence: 99%

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Peripheral injections of melanin-concentrating hormone receptor 1 antagonist S38151 decrease food intake and body weight in rodent obesity models

Della‐Zuana¹,

Audinot²,

Levenez³

et al. 2012

Front. Endocrin.

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The compound S38151 is a nanomolar antagonist that acts at the melanin-concentrating hormone receptor 1 (MCH1). S38151 is more stable than its purely peptide counterpart, essentially because of the blockade of its N-terminus. Therefore, its action on various models of obesity was studied. Acute intra-cerebroventricular (i.c.v.) administration of S38151 in wild-type rats counteracted the effect of the stable precursor of melanin-concentrating hormone (MCH), NEI-MCH, in a dose-dependent manner (from 0.5 to 50 nmol/kg). In genetically obese Zucker fa/fa rats, daily i.c.v. administration of S38151 induced dose-dependent (5, 10, and 20 nmol/kg) inhibition of food intake, water intake, and body weight gain, as well as increased motility (maximal effect observed at 20 nmol/kg). In Zucker fa/fa rats, intraperitoneal injection of S38151 (30 mg/kg) induced complete inhibition of food consumption within 1 h. Daily intraperitoneal injection of S38151 (10 and 30 mg/kg) into genetically obese ob/ob mice or diet-induced obese mice is able to limit body weight gain. Furthermore, S38151 administration (10 and 30 mg/kg) does not affect food intake, water intake, or body weight gain in MCHR1-deleted mice, demonstrating that its effects are linked to its interaction with MCH1. These results validate MCH1 as a target of interest in obesity. S38151 cannot progress to the clinical phase because it is still too poorly stable in vivo.

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Pharmacological Treatment of Obesity

Kabra¹,

Kabra²,

Tschöp³

et al. 2012

Sleep Loss and Obesity

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S38151 [p-guanidinobenzoyl-[Des-Gly10]-MCH(7-17)] is a potent and selective antagonist at the MCH1 receptor and has anti-feeding properties in vivo

Cited by 9 publications

References 39 publications

Recent Updates on the Melanin-Concentrating Hormone (MCH) and Its Receptor System: Lessons from MCH1R Antagonists

Recent Updates on the Melanin-Concentrating Hormone (MCH) and Its Receptor System: Lessons from MCH1R Antagonists

Peripheral injections of melanin-concentrating hormone receptor 1 antagonist S38151 decrease food intake and body weight in rodent obesity models

Pharmacological Treatment of Obesity

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