10.1021/jm800291b.s001
Bettina Proneth
Bettina
Proneth
Irina D. Pogozheva
Irina D.
Pogozheva
Federico P. Portillo
Federico P.
Portillo
Henry I. Mosberg
Henry I.
Mosberg
Carrie Haskell-Luevano
Carrie
Haskell-Luevano
Melanocortin Tetrapeptide Ac-His-DPhe-Arg-Trp-NH<sub>2</sub> Modified at the Para Position of the Benzyl Side Chain (DPhe): Importance for Mouse Melanocortin-3 Receptor Agonist versus Antagonist Activity
American Chemical Society
2008
nanomolar agonist pharmacology
SAR
mMC 3R
MC 3R MC 4R
MC 3R
15 DPhe 7
mMC 4R
Benzyl Side Chain
mMC 3R agonist
2008-09-25 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Melanocortin_Tetrapeptide_Ac_His_DPhe_Arg_Trp_NH_sub_2_sub_Modified_at_the_Para_Position_of_the_Benzyl_Side_Chain_DPhe_Importance_for_Mouse_Melanocortin_3_Receptor_Agonist_versus_Antagonist_Activity/2911591
The melanocortin-3 and -4 receptors (MC3R, MC4R) have been implicated in energy homeostasis and obesity. Whereas the physiological role of the MC4R is extensively studied, little is known about the MC3R. One caveat is the limited availability of ligands that are selective for the MC3R. Previous studies identified Ac-His-DPhe(p-I)-Arg-Trp-NH<sub>2</sub>, which possessed partial agonist/antagonist pharmacology at the mMC3R while retaining full nanomolar agonist pharmacology at the mMC4R. These data allowed for the hypothesis that the DPhe position in melanocortin tetrapeptides can be used to examine ligand side-chain determinants important for differentiation of mMC3R agonist versus antagonist activity. A series of 15 DPhe<sup>7</sup> modified Ac-His-DPhe<sup>7</sup>-Arg-Trp-NH<sub>2</sub> tetrapeptides has been synthesized and pharmacologically characterized. Most notable results include the identification of modifications that resulted in potent antagonists/partial agonists at the mMC3R and full, potent agonists at the mMC4R. These SAR studies provide experimental evidence that the molecular mechanism of antagonism at the mMC3R differentiates this subtype from the mMC4R.