MC-4R Agonist 1
Brand Name: Vulcanchem
CAS No.:
VCID: VC16502022
InChI: InChI=1S/C30H38ClF2N3O2/c1-18(34-19(2)37)25-14-21(31)6-8-23(25)20-10-12-35(13-11-20)29(38)27-17-36(30(3,4)5)16-26(27)24-9-7-22(32)15-28(24)33/h6-9,14-15,18,20,26-27H,10-13,16-17H2,1-5H3,(H,34,37)/t18?,26-,27+/m0/s1
SMILES:
Molecular Formula: C30H38ClF2N3O2
Molecular Weight: 546.1 g/mol
Cat. No.: VC16502022
The MC4R is a class A G-protein-coupled receptor (GPCR) that binds endogenous agonists like α-melanocyte-stimulating hormone (α-MSH) and synthetic ligands such as setmelanotide. A landmark study resolved the active-state MC4R structure at 3.4 Å resolution using a conformation-selective nanobody (pN162) stabilized in a chimeric MC4R-β2AR construct. The structure revealed that pN162 binds deeply within the orthosteric pocket, engaging transmembrane helices 3, 5, 6, and 7 through hydrophobic and polar interactions. This binding mode stabilizes the receptor’s active conformation, enabling potent and selective agonism distinct from peptide ligands like setmelanotide, which exhibit promiscuity across melanocortin receptor subtypes.
Setmelanotide (RM-493), a cyclic peptide agonist, demonstrates a 20-fold higher potency than endogenous α-MSH in activating MC4R mutants associated with genetic obesity. Homology modeling and docking studies suggest that setmelanotide interacts with both orthosteric and allosteric sites, including extracellular loops 2 and 3, to stabilize active-state conformations even in receptors with loss-of-function mutations. For example, in mutants like Ser127Leu and Arg165Trp, setmelanotide’s rigid cyclic structure facilitates interactions with conserved residues (e.g., Asp126 and Asn123) that restore downstream signaling.
A 2025 Phase 2 study evaluated the co-administration of MC4R agonist bremelanotide (1.25 mg daily) with tirzepatide (2.5 mg weekly), a GLP-1/GIP receptor agonist, in 113 patients with obesity. After 8 weeks, the co-administration group achieved a 4.4% weight reduction compared to 1.6% with tirzepatide alone (p< 0.0001). Notably, 40% of patients in the combination group reached ≥5% weight loss versus 13% in the monotherapy group (p< 0.05).
Table 1: Weight Loss Outcomes in Phase 2 Co-Administration Study
While GLP-1 agonists like semaglutide achieve 15–20% weight loss, 67% of patients discontinue treatment due to gastrointestinal side effects or cost. MC4R agonists target a distinct pathway—enhancing satiety signals rather than delaying gastric emptying—offering a complementary mechanism with potential synergistic effects.
Traditional peptide agonists (e.g., setmelanotide) activate MC1R and MC3R, leading to hyperpigmentation and cardiovascular effects. Nanobodies like pN162 and MC1R-sparing agents (RM-718) exhibit >100-fold selectivity for MC4R, reducing off-target risks.
MC4R agonists are being explored for hypothalamic obesity, Prader-Willi syndrome, and monogenic MC4R deficiencies. Rhythm Pharmaceuticals plans to initiate trials in hypothalamic obesity cohorts in 2025, leveraging RM-718’s CNS penetration to address hyperphagia.
The synergy between MC4R agonists and GLP-1/GIP therapies suggests that tailored regimens could optimize weight loss while minimizing side effects. Upcoming Phase 3 trials will evaluate long-term safety and efficacy in diverse populations.
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