Short segment of human melanin-concentrating hormone that is sufficient for full activation of human melanin-concentrating hormone receptors 1 and 2.
Human melanin-concentrating hormone (hMCH) is a potent but nonselective agonist at human melanin-concentrating hormone receptors 1 and 2 (hMCH-1R and hMCH-2R, respectively). To determine the structural features of this neuropeptide which are necessary for efficient binding to and activation of the receptors, Ala-substituted, open-chain, and truncated analogues were synthesized and tested in the binding assays in CHO cells expressing hMCH-1R and hMCH-2R, and in functional assays measuring the level of intracellular calcium mobilization in human HEK-293 cells expressing these receptors. A compound consisting merely of the cyclic core of hMCH with the Arg attached to the N-terminus of the disulfide ring was found to activate both hMCH-1R and hMCH-2R about as effectively as full-length hMCH. Thus, the sequence Arg-cyclo(S-S)(Cys-Met-Leu-Gly-Arg-Val-Tyr-Arg-Pro-Cys) appears to constitute the "active core" that is necessary for agonist potency at hMCH-1R and hMCH-2R. A potent and approximately 4-fold more selective agonist at hMCH-1R than at hMCH-2R is also reported.
Bednarek
M A
MA
Department of Medicinal Chemistry, Merck Research Laboratories, R50G-141, Rahway, New Jersey 07065, USA. maria_bednarek@merck.com
Feighner
S D
SD
Hreniuk
D L
DL
Palyha
O C
OC
Morin
N R
NR
Sadowski
S J
SJ
MacNeil
D J
DJ
Howard
A D
AD
Van der Ploeg
L H
LH
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007028:Hypothalamic Hormones / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D007536:Isomerism; D008543:Melanins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000502:physiology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000502:physiology; D010907:Pituitary Hormones / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled; D011979:Receptors, Pituitary Hormone / Q000819:agonists / Q000378:metabolism*
D004220:Disulfides; D007028:Hypothalamic Hormones; C431280:MCHR2 protein, human; D008543:Melanins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010907:Pituitary Hormones; D043562:Receptors, G-Protein-Coupled; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; C019463:melanin-concentrating hormone; D003545:Cysteine; D000409:Alanine