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Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands
- Source :
- Molecules, Vol 24, Iss 8, p 1463 (2019), Molecules, Volume 24, Issue 8
- Publication Year :
- 2019
- Publisher :
- MDPI AG, 2019.
-
Abstract
- The five melanocortin receptors (MC1R&ndash<br />MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.
- Subjects :
- Agonist
medicine.drug_class
Pharmaceutical Science
Pharmacology
MC4R
01 natural sciences
Energy homeostasis
Analytical Chemistry
Biological pathway
lcsh:QD241-441
03 medical and health sciences
lcsh:Organic chemistry
Drug Discovery
medicine
Physical and Theoretical Chemistry
Receptor
030304 developmental biology
Melanocortins
0303 health sciences
Tetrapeptide
Chemistry
Organic Chemistry
MC3R
tetrapeptides
mixed pharmacology
melanocortins
3. Good health
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Chemistry (miscellaneous)
Knockout mouse
Molecular Medicine
Melanocortin
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 24
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecules
- Accession number :
- edsair.doi.dedup.....a43f37587226cfa8319bcb3f142a97b4