Article
Peptide and small molecules rescue the functional activity and agonist potency of dysfunctional human melanocortin-4 receptor polymorphisms.
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA.
Biochemistry (impact factor:
3.42).
08/2007;
46(28):8273-87.
DOI:10.1021/bi7007382
Source: PubMed
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Citations (0)
- Cited In (4)
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Article: The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology.
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ABSTRACT: The melanocortin-4 receptor (MC4R) was cloned in 1993 by degenerate PCR; however, its function was unknown. Subsequent studies suggest that the MC4R might be involved in regulating energy homeostasis. This hypothesis was confirmed in 1997 by a series of seminal studies in mice. In 1998, human genetic studies demonstrated that mutations in the MC4R gene can cause monogenic obesity. We now know that mutations in the MC4R are the most common monogenic form of obesity, with more than 150 distinct mutations reported thus far. This review will summarize the studies on the MC4R, from its cloning and tissue distribution to its physiological roles in regulating energy homeostasis, cachexia, cardiovascular function, glucose and lipid homeostasis, reproduction and sexual function, drug abuse, pain perception, brain inflammation, and anxiety. I will then review the studies on the pharmacology of the receptor, including ligand binding and receptor activation, signaling pathways, as well as its regulation. Finally, the pathophysiology of the MC4R in obesity pathogenesis will be reviewed. Functional studies of the mutant MC4Rs and the therapeutic implications, including small molecules in correcting binding and signaling defect, and their potential as pharmacological chaperones in rescuing intracellularly retained mutants, will be highlighted.Endocrine reviews 02/2010; 31(4):506-43. · 19.76 Impact Factor -
Article: Obesity Drug Update: The Lost Decade?
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ABSTRACT: The growing worldwide obesity epidemic and obesity-related disorders present a huge unmet medical need for safe and effective anti-obesity medications. The discovery of leptin in 1994 was rapidly succeeded by a wave of related discoveries leading to the elaboration of a hypothalamic melanocortinergic neuronal circuit regulated by leptin and other central and peripheral signaling molecules to control energy homeostasis. The identification of specific neuronal subtypes along with their unique connections and expression products generated a rich target menu for anti-obesity drug discovery programs. Over the course of the last decade, several new chemical entities aimed at these targets have reached various stages or successfully completed the drug discovery/regulatory process only to be dropped or taken off the market. There are now in fact fewer options for anti-obesity drug therapies in late 2010 than were available in 2000. The challenge to discover safe and effective anti-obesity drugs is alive and well.Pharmaceuticals. 01/2010; -
Article: Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR.
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ABSTRACT: By use of a solid-phase synthetic approach, a bioactive reverse turn heterocycle was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R-MC5R) are G-protein-coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis. Herein, we report novel analogues of the chimeric AGRP-melanocortin peptide template integrated with a small molecule moiety to probe the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nanomolar potency. Biophysical structural analysis [2D (1)H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small molecule hybrids possessed increased flexibility and fewer discrete conformational families compared to the reference peptide and result in a novel template for further structure-function studies.Journal of Medicinal Chemistry 02/2011; 54(5):1379-90. · 4.80 Impact Factor
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Keywords
13 polymorphic hMC4Rs
70 human melanocortin-4 receptor
amino-2-naphtylcarboxylic acid
antagonist ligands
chimeric AGRP-melanocortin
cognate endogenous agonist
endogenous agonist potency
Genetic studies
hMC4R polymorphic agonist response
hMC4R polymorphisms
hMC4Rs
homozygous forms
melanocortin pathway
morbidly obese human patients
normal weight control patients
obese human phenotype
small molecules
small molecules JB25
subnanomolar agonist potency
synthetic peptides
