title: Structure-activity relationships of peptides incorporating a bioactive reverse-turn heterocycle at the melanocortin receptors: identification of a 5800-fold mouse melanocortin-3 receptor (mMC3R) selective antagonist/partial agonist versus the mouse melanocortin-4 receptor (mMC4R).
abstract: The melanocortin-3 (MC3) and melanocortin-4 (MC4) receptors regulate energy homeostasis, food intake, and associated physiological conditions. The melanocortin-4 receptor (MC4R) has been studied extensively. Less is known about specific physiological roles of the melanocortin-3 receptor (MC3R). A major obstacle to this lack of knowledge is attributed to a limited number of identified MC3R selective ligands. We previously reported a spatial scanning approach of a 10-membered thioether-heterocycle ring incorporated into a chimeric peptide template that identified a lead nM MC4R ligand. Upon the basis of those results, 17 compounds were designed and synthesized that focused upon modification in the pharmacophore domain. Notable results include the identification of a 0.13 nM potent 5800-fold mMC3R selective antagonist/slight partial agonist versus a 760 nM mMC4R full agonist (ligand 11). Biophysical experiments (two-dimensional (1)H NMR and computer-assisted molecular modeling) of this ligand resulted in the identification of an inverse γ-turn secondary structure in the ligand pharmacophore domain.
authors: Department of Medicinal Chemistry and Pharmacodynamics, University of Florida, Gainesville, Florida 32610, United States.
authors: Anamika
authors: A
authors: Singh
authors: Marvin
authors: M
authors: Dirain
authors: Rachel
authors: R
authors: Witek
authors: James R
authors: JR
authors: Rocca
authors: Arthur S
authors: AS
authors: Edison
authors: Carrie
authors: C
authors: Haskell-Luevano
mesh_terms: D000818:Animals; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D044101:Receptors, Melanocortin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D044101:Receptors, Melanocortin