Melanin-Concentrating Hormone

Chemical Identity

Property	Value
Name	Melanin-Concentrating Hormone
Gene	PMCH (chromosome 12q23)
Sequence	Asp-Phe-Leu-Met-His-Asp-Val-Met-Thr-Arg-Cys-Met-Glu-Val-Gly-Arg-Val-Tyr-Gln-Cys-Pro-Val
Length	19 amino acids (mature form)
Disulfide Bond	Cys11-Cys19 (cyclic)
MW	2286.7 Da
PDB Structures	1DF6 (NMR in SDS)

Distribution

Central Nervous System

• Lateral hypothalamus: Primary site (MCH neurons)
• Perifornical area: Dense projection
• Zona incerta: Projection
• Brainstem: Sparse projection

Receptors

Receptor	Gene	Distribution	Primary Effects
MCHR1	MCHR1	Brain (widespread)	Feeding, energy storage
MCHR2	MCHR2	Brain (low expression)	Function unclear (non-functional in humans)

Physiological Functions

Appetite Stimulation

• MCH is a potent orexigenic neuropeptide
• MCH neurons are activated by fasting, inhibited by leptin
• MCHR1 knockout mice: Lean, hypophagic, hypomotile

Energy Storage

• Promotes fat storage (lipogenesis)
• Inhibits energy expenditure
• MCH overexpression: Obesity in transgenic mice

Other Functions

• Sleep: MCH neurons active during REM sleep
• Anxiety: MCHR1 activation reduces anxiety
• Aggression: MCH modulates aggressive behavior

Clinical Significance

MCHR1 as Anti-Obesity Target

• Rationale: MCHR1 antagonists could reduce feeding and increase expenditure
• Challenges: Selectivity (many off-target effects), CNS penetration
• Status: Most programs discontinued due to side effects

MCHR1 Antagonists

Drug	Status	Notes
SNAP-7941	Discontinued	Anxiety, obesity
GW803430	Discontinued	Obesity
ML002537-46	Research	Research tool

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• Disulfide formation: Air oxidation
• Purification: RP-HPLC
• Characterization: Mass spectrometry, NMR

References

1. Qu D, et al. “A role for melanin-concentrating hormone in the central regulation of feeding behaviour.” Nature 380:243-247, 1996. doi:10.1126/science.260.5105.294
2. Ludwig DS, et al. “Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance.” Journal of Clinical Investigation 107:379-386, 2001.
3. Saito Y, et al. “Melanocortin-3 receptor and feeding behavior.” Annals of the New York Academy of Sciences 897:145-156, 1999.
4. Shimada M, et al. “MCH and feeding behavior.” Peptides 22:2169-2174, 2001.
5. Chambers J, et al. “Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1.” Nature 400:261-265, 1999.