scholarly journals A Small Molecule Agonist THIQ as a Novel Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants

2014 ◽  
Vol 10 (8) ◽  
pp. 817-824 ◽  
Author(s):  
Hui Huang ◽  
Ya-Xiong Tao
Keyword(s):  
Small Molecule ◽  
Melanocortin 4 Receptor

Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans

2010 ◽  
Vol 53 (8) ◽  
pp. 3183-3197 ◽  
Author(s):  
Mark I. Lansdell ◽  
David Hepworth ◽  
Andrew Calabrese ◽  
Alan D. Brown ◽  
Julian Blagg ◽  
...  
Keyword(s):  
Pilot Study ◽  
Sexual Dysfunction ◽  
Small Molecule ◽  
Receptor Agonist ◽  
Melanocortin 4 Receptor

Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

2004 ◽  
Vol 1000 (1-2) ◽  
pp. 64-71 ◽  
Author(s):  
David Cepoi ◽  
Teresa Phillips ◽  
Mary Cismowski ◽  
Val S Goodfellow ◽  
Nick Ling ◽  
...  
Keyword(s):  
Small Molecule ◽  
Energy Homeostasis ◽  
Melanocortin 4 Receptor

scholarly journals The Regulation of Feeding and Metabolic Rate and the Prevention of Murine Cancer Cachexia with a Small-Molecule Melanocortin-4 Receptor Antagonist

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2766-2773 ◽  
Author(s):  
Stacy Markison ◽  
Alan C. Foster ◽  
Chen Chen ◽  
Gregor B. Brookhart ◽  
Amy Hesse ◽  
...  
Keyword(s):  
Metabolic Rate ◽  
Receptor Antagonist ◽  
Small Molecule ◽  
Cancer Cachexia ◽  
Melanocortin 4 Receptor

Synthesis and biological evaluation of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R)

2004 ◽  
Vol 14 (14) ◽  
pp. 3721-3725 ◽  
Author(s):  
Thomas H Marsilje ◽  
Jonathan B Roses ◽  
Emily F Calderwood ◽  
Stephen G Stroud ◽  
Nancy E Forsyth ◽  
...  
Keyword(s):  
Small Molecule ◽  
Biological Evaluation ◽  
Melanocortin 4 Receptor ◽  
Synthesis And Biological Evaluation

scholarly journals Structural insights into ligand recognition and activation of the melanocortin-4 receptor

2021 ◽  
Author(s):  
Yan Zhang ◽  
Huibing Zhang ◽  
Li-Nan Chen ◽  
Dehua Yang ◽  
Chunyou Mao ◽  
...  
Keyword(s):  
Small Molecule ◽  
Energy Homeostasis ◽  
Structural Information ◽  
Sequence Similarity ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Receptor Subtype ◽  
High Sequence Similarity ◽  
Subtype Selectivity ◽  
Melanocortin 4 Receptor

Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning receptor activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric Gs protein stimulated by the endogenous peptide α-MSH, FDA-approved drugs afamelanotide (Scenesse™) and bremelanotide (Vyleesi™), and selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.

scholarly journals Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1892 ◽  
Author(s):  
Shubh Sharma ◽  
Alastair S. Garfield ◽  
Bhavik Shah ◽  
Patrick Kleyn ◽  
Ilia Ichetovkin ◽  
...  
Keyword(s):  
Small Molecule ◽  
Receptor Activation ◽  
Mechanistic Studies ◽  
Therapeutic Targeting ◽  
Activation Kinetics ◽  
Melanocortin 4 Receptor ◽  
Pathway Activation ◽  
Signaling Events ◽  
Biased Signaling ◽  
Targeting Strategy

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.

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