SAR of Melanin-concentration Hormone (MCH), an Important Regulatory Hormone in Feeding Behavior

Danho, Waleed; Swistok, Joseph; Khan, Wajiha; Truitt, Theresa; Aglione, Anthony; Garippa, Ralph; Xu, Kui; Chen, Yingsi; Xiang, Qing; Kochan, Jarema; Falcioni, Fiorenza

doi:10.1007/978-94-010-0464-0_328

Cited by 3 publications

(7 citation statements)

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“…Aequorin Bioluminescence Functional Assays (24,26,27)-For the functional receptor activation assays, stable cell lines expressing either the MCH-1R or the MCH-2R and the aequorin reporter protein were used. The assays were performed on a Luminoskan RT luminometer (Labsystems Inc., Gaithersburg, MD) controlled by custom software written for a PC-compatible computer.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Biological Evaluation in Vitro of a Selective, High Potency Peptide Agonist of Human Melanin-concentrating Hormone Action at Human Melanin-concentrating Hormone Receptor 1

Bednarek

Tan

Hreniuk

et al. 2002

Journal of Biological Chemistry

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Human melanin-concentrating hormone (hMCH) is a nonselective natural ligand for the human melanin-concentrating hormone receptors: hMCH-1R and hMCH-2R. Similarly, the smaller peptide encompassing the disulfide ring and 50 ‫؍‬ 47 nM) with more than 200-fold selectivity with respect to hMCH-2R. Apparently, these structural changes in positions 6 and 10 results in peptide conformations that allow for efficient interactions with hMCH-1R but are unfavorable for molecular recognition at hMCH-2R.In the last couple of years, melanin-concentrating hormone (MCH) 1 emerged as an important regulator of feeding behavior in rodents (1-7). Similarly to neuropeptide Y, this hormone stimulates appetite in rats when injected intracerebroventricularly, and this orexigenic effect is inhibited by anorectic peptides such as ␣-melanocyte stimulating hormone, glucagon-like peptide 1, and neurotensin (1-7). Additionally, in the hypothalamus of genetically obese (ob/ob) and fasting mice, the level of MCH messenger RNA is elevated, and the metabolic rate of mice lacking MCH is increased. MCH (see Structure 1 for human/rat MCH) also appears to be involved in other biological functions such as regulation of the hypothalamic-pituitarythyroid axis. In humans, this 19-amino acid cyclic peptide is found in the brain, in the lateral hypothalamus and the zona incerta, and acts through specific receptors (8 -12). At present, two receptors are known with which hMCH interacts: hMCH-1R and hMCH-2R (13-23). These receptors are members of the family of G-protein-coupled receptors and their activation leads to mobilization of intracellular calcium. Binding of hMCH to hMCH-1R results in reduction of forskolin-elevated cyclic AMP levels, but binding to hMCH-2R does not cause this effect. The physiological role of hMCH-2R is less well understood than the physiological role of hMCH-1R, but the presence of the MCH-2R messenger RNA in the brain regions implicated in the regulation of body weight suggests that this receptor might also be involved in the regulation of feeding behavior (19 -23).To understand and separate the physiological functions of the MCH receptors, selective agonists are required, because hMCH is a nonspecific natural ligand for both hMCH-1R and hMCH-2R. Similarly, the synthetic ligands reported in the literature do not distinguish between the receptors (13-23).Our previous structure-function studies on hMCH yielded a cyclic peptide consisting of the disulfide ring and Arg 6 of hMCH: the so-called "active core" of hMCH with the four residues, Arg 6 , Met 8 , Arg 11 , and Tyr 13 , critical for molecular recognition at hMCH-1R and hMCH-2R (24 -27). This compound, Ac-hMCH(6 -16)-NH 2 (Structure 2), was equipotent to the fulllength hMCH at both receptors. Moreover, at hMCH-1R, an analog of Ac-hMCH(6 -16)-NH 2 with D-Arg in position 6 was as potent as the parent compound, but, at hMCH-2R, this analog was a noticeably weaker agonist. The D-Arg 6 compound was the first described peptide agonist with enhanced hMCH-1R selectivity with respect to ...

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Section: Methodsmentioning

confidence: 99%

Synthesis and Biological Evaluation in Vitro of a Selective, High Potency Peptide Agonist of Human Melanin-concentrating Hormone Action at Human Melanin-concentrating Hormone Receptor 1

Bednarek

Tan

Hreniuk

et al. 2002

Journal of Biological Chemistry

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“…Danho and coworkers stated [42] that the 60 hMCH analogs prepared by the Roche group were approximately 2-fold less potent at hMCH-2R than at hMCH-1R (the structures of these compounds and their binding and functional data were not disclosed). The same compounds were from 4 to 5-fold less potent at the mouse MCH-1R than at the human counterpart.…”

Section: Human Mch Receptor 1 Agonistsmentioning

confidence: 95%

“…The majority of the hMCH-derived agonists described in the literature were either pan-agonists active at both hMCH receptors, or hMCH-1R agonists for which in vitro binding and functional data at hMCH-2R were not collected or reported [36][37][38][39]42].…”

Section: Human Mch Receptor 1 Agonistsmentioning

confidence: 99%

“…In a later poster presentation, a group from Roche [42] reported that a short analog of hMCH, the hMCH(6-16) compound encompassing in its structure the same amino acid residues as peptide 9 (Fig. 4), retained the agonist potency of the full-length parent peptide, however, no binding or calcium release measurement data at hMCH-1R or hMCH-2R were provided for the smaller compound.…”

Section: Introductionmentioning

confidence: 96%

“…Limited binding or activation data at hMCH-1R were provided for these analogs. It was concluded that the intact disulfide ring with Met 8 , Arg 11 , Tyr 13 and the unaltered chirality of residues in the ring structure are critical for agonist activity at hMCH-1R [42].…”

Section: Introductionmentioning

confidence: 99%

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Peptide Ligands for the Melanin-Concentrating Hormone (MCH) Receptor 1

Bednarek¹

2007

CTMC

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The melanin-concentrating hormone receptor 1 (MCH-1R) has been recognized as a receptor which mediates effects of the endogenous melanin-concentrating hormone (MCH) on appetite and body weight gain in rodents. In the last several years, a number of hMCH analogs have been designed which were potent and selective ligands for hMCH-1R. These peptidic agonists and antagonists have served as research tools in animal studies that showed a key role of the MCH-1R in the development of obesity and proved that MCH-1R antagonism can produce anti-obesity effects in rodents.

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Synthesis and Biological Evaluation in Vitro of Selective, High Affinity Peptide Antagonists of Human Melanin-Concentrating Hormone Action at Human Melanin-Concentrating Hormone Receptor 1

et al. 2002

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Human melanin-concentrating hormone (hMCH) and many of its analogues are potent but nonspecific ligands for human melanin-concentrating hormone receptors 1 and 2 (hMCH-1R and hMCH-2R). To differentiate between the physiological functions of these receptors, selective antagonists are needed. In this study, analogues of Ac-Arg(6)-cyclo(S-S)(Cys(7)-Met(8)-Leu(9)-Gly(10)-Arg(11)-Val(12)-Tyr(13)-Arg(14)-Pro(15)-Cys(16))-NH(2), a high affinity but nonselective agonist at hMCH-1R and hMCH-2R, were prepared and tested in binding and functional assays on cells expressing these receptors. In the new analogues, 5-aminovaleric acid (Ava) was incorporated in place of the Leu(9)-Gly(10) and/or Arg(14)-Pro(15) segments of the disulfide ring. Several of these compounds turned out to be high affinity antagonists selective for hMCH-1R. Moreover, even at micromolar concentrations, they were devoid of agonist potency at both hMCH receptors and not effective as hMCH-2R antagonists. For example, peptide 14, Gva(6)- cyclo(S-S)(Cys(7)-Met(8)-Leu(9)-Gly(10)-Arg(11)-Val(12)-Tyr(13)-Ava(14,15)-Cys(16))-NH(2), (Gva = 5-guanidinovaleric acid), was a full competitive hMCH-1R antagonist (IC(50) = 14 nM, K(B) = 0.9 nM) with more than 1000-fold selectivity over hMCH-2R. Examination of various compounds with Ava in positions 9,10 and/or 14,15 revealed that the Leu(9)-Gly(10) and Arg(14)-Pro(15) segments of the disulfide ring are the principal structural elements determining hMCH-1R selectivity and ability to act as a hMCH-1R antagonist.

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SAR of Melanin-concentration Hormone (MCH), an Important Regulatory Hormone in Feeding Behavior

Cited by 3 publications

References 4 publications

Synthesis and Biological Evaluation in Vitro of a Selective, High Potency Peptide Agonist of Human Melanin-concentrating Hormone Action at Human Melanin-concentrating Hormone Receptor 1

Synthesis and Biological Evaluation in Vitro of a Selective, High Potency Peptide Agonist of Human Melanin-concentrating Hormone Action at Human Melanin-concentrating Hormone Receptor 1

Peptide Ligands for the Melanin-Concentrating Hormone (MCH) Receptor 1

Synthesis and Biological Evaluation in Vitro of Selective, High Affinity Peptide Antagonists of Human Melanin-Concentrating Hormone Action at Human Melanin-Concentrating Hormone Receptor 1

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