Melanocortin Antagonist Tetrapeptides with Minimal Agonist Activity at the Mouse Melanocortin-3 Receptor

Abstract

The melanocortin system regulates many important functions in the body. There are five melanocortin G protein-coupled receptor subtypes known to date. Herein, we report a structure-activity relationship (SAR) study of a tetrapeptide lead discovered through a double substitution strategy at the melanocortin core His-Phe-Arg-Trp sequence. Several compounds were identified with micromolar agonist activity at the mouse melanocortin-1 (mMC1R) and mouse melanocortin-5 receptor (mMC5R) subtypes, weak antagonist activity at the mouse melanocortin-3 receptor (mMC3R), and potent antagonist activity at the mouse melanocortin-4 receptor (mMC4R). Two compounds (2 and 3) were nanomolar mMC4R antagonists with no mMC3R antagonist activity observed. Additionally, we identified three tetrapeptide MC3R antagonists (1, 6, and 7) that possess minimal mMC3R agonist activity only at 100 μM, not commonly observed for mMC3R/mMC4R antagonists. These novel molecular templates have the potential as molecular probes to better differentiate the roles of the centrally expressed MC3 and MC4 receptors.

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

“…From these search parameters, three studies reported selective pA 2 values at two melanocortin receptors (mMC3R and mMC4R) and reported functional agonist EC 50 values for the other two receptors (mMC1R and mMC5R, Table 3) [132-134]. For the sake of clarity, antagonists in Table 3 were divided into two sections: ligands with antagonist activity at the mMC4R but no agonist or antagonist activity observed at the mMC3R at concentrations up to 10 μM (pA 2 < 5) and antagonists that were active at the mMC3R and mMC4R.…”

“…The antagonists reported by Doering et al . were derivatives of the tetrapeptide Ac-Trp-DPhe( p -I)-Arg-Trp-NH 2 [132]. Scaffolds reported by Ericson et al .…”

Investigating Metabolic Gender Differences with Melanocortin Antagonist SKY 2-23-7

“…SKY 2-23-7 was characterized as a weak antagonist (pA2=5.43±0.16) at the mMC3R and a strong antagonist (pA2=7.83±0.16) at the mMC4R (Figure 2). Distinctly there was minimal mMC3R agonist activity up to 100 µM which is not commonly observed for a mMC3R/mMC4R antagonist such as SHU9119 [11]. The current study investigated the in vivo effects of this unique pharmacology via intracerebroventricular (ICV) administration of SKY 2-23-7 in male and female mice which gave evidence of sex specific differences.…”

“…SKY 2-23-7 is a tetrapeptide which was identified in our laboratory with the sequence Ac-Trp-(p-I)DPhe-Arg-Trp-NH2 ( Figure 1) [11]. It was discovered through a double substitution strategy of the melanocortin core His-Phe-Arg-Trp sequence.…”

“…The current study investigated the in vivo effects of this unique pharmacology via intracerebroventricular (ICV) administration of SKY 2-23-7 in male and female mice which gave evidence of sex specific differences. at the mMC3R and mMC4R [11]. The pA2 values were found by a Schild analysis [12].…”