4‐Acylamino‐ and 4‐Ureidobenzamides as Melanin‐Concentrating Hormone (MCH) Receptor 1 Antagonists

Receveur, Jean-Marie; Bjurling, Emelie; Ulven, Trond; Little, Paul B.; Noerregaard, Pia K.; Hoegberg, Thomas

doi:10.1002/chin.200503102

Cited by 6 publications

(8 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In two other receptors (MCHR1 and MCHR2), an aspartate is observed at the preceding position (Asp 3.32 ). The concomitant presence of an acidic residue in TM3 and an aromatic cluster in TMs 5 and 6 (excepted for TRFR) explains why many receptor antagonists from this cluster (e.g., MCHR1) can be derived from biogenic amine receptor ligands 155…”

Section: Resultsmentioning

confidence: 99%

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

et al. 2005

View full text Add to dashboard Cite

The amino acid sequences of 369 human nonolfactory G-protein-coupled receptors (GPCRs) have been aligned at the seven transmembrane domain (TM) and used to extract the nature of 30 critical residues supposed--from the X-ray structure of bovine rhodopsin bound to retinal--to line the TM binding cavity of ground-state receptors. Interestingly, the clustering of human GPCRs from these 30 residues mirrors the recently described phylogenetic tree of full-sequence human GPCRs (Fredriksson et al., Mol Pharmacol 2003;63:1256-1272) with few exceptions. A TM cavity could be found for all investigated GPCRs with physicochemical properties matching that of their cognate ligands. The current approach allows a very fast comparison of most human GPCRs from the focused perspective of the predicted TM cavity and permits to easily detect key residues that drive ligand selectivity or promiscuity.

show abstract

Section: Resultsmentioning

confidence: 99%

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Chemogenomic classification of GPCR binding sites proposes to generate dendograms that reflect selectivity profiles for individual ligands, and from this it follows that pharmacological relationships can be extrapolated between different targets that have similar binding pockets/sites. In the literature, relationships based on the similarities of GPCR ligand binding sites have been used successfully in the design of focused compound libraries, ,− lead generation, , ligand inference, , and selectivity profiling . Here, we have assessed the utility of chemogenomic classification of GPCRs at the level of the TM bundle binding pocket of Rhodopsin family GPCRs and the aminergic receptor endogenous ligand binding (sub)site.…”

Section: Discussionmentioning

confidence: 99%

“…While there have been a modest number of applications of the chemogenomics approach to GPCRs − and they have proven quite successful, more widespread use has been tempered by the relative lack of structural information available to support drug design. The X-ray crystal structure of bovine Rhodopsin has been available for some time and receptor homology models have been used for many years, but it has taken until 2007 for the structure of a GPCR drug target to be solved.…”

Section: Introductionmentioning

confidence: 99%

Definition of the G Protein-Coupled Receptor Transmembrane Bundle Binding Pocket and Calculation of Receptor Similarities for Drug Design

Gloriam

Foord²,

Blaney³

et al. 2009

J. Med. Chem.

View full text Add to dashboard Cite

Recent advances in structural biology for G-protein-coupled receptors (GPCRs) have provided new opportunities to improve the definition of the transmembrane binding pocket. Here a reference set of 44 residue positions accessible for ligand binding was defined through detailed analysis of all currently available crystal structures. This was used to characterize pharmacological relationships of Family A/Rhodopsin family GPCRs, minimizing evolutionary influence from parts of the receptor that do not generally affect ligand binding. The resultant dendogram tended to group receptors according to endogenous ligand types, although it revealed subdivision of certain classes, notably peptide and lipid receptors. The transmembrane binding site reference set, particularly when coupled with a means of identifying the subset of ligand binding residues, provides a general paradigm for understanding the pharmacology/selectivity profile of ligands at Family A GPCRs. This has wide applicability to GPCR drug design problems across many disease areas.

show abstract

“…Of 1448 approved small molecules, 131 approved biologics (termed biotech in the database), and 84 nutraceuticals, 437 (26%) have their activity linked to GPCRs. There are 365 nonolfactory GPCRs that are typically thought of as being potential drug targets, of which 284 are categorized as Family A/rhodopsin, 15 Family B/secretin, 33 Family/adhesion, 22 Family C/ glutamate, and 11 Family F/frizzled receptors. 8 Allowing for two modalities, agonists, and antagonists, there are perhaps crudely 365 × 2 = 730 potential drug targets in the family.…”

Section: Marketed Drugsmentioning

confidence: 99%

Are GPCRs Still a Source of New Targets?

Garland

2013

SLAS Discovery

135

View full text Add to dashboard Cite

G-protein-coupled receptors (GPCRs) still offer enormous scope for new therapeutic targets. Currently marketed agents are dominated by those with activity at aminergic receptors and yet they account for only ~10% of the family. Progress up until now with other subfamilies, notably orphans, Family A/peptide, Family A/lipid, Family B, Family C, and Family F, has been, at best, patchy. This may be attributable to the heterogeneous nature of GPCRs, their endogenous ligands, and consequently their binding sites. Our appreciation of receptor similarity has arguably been too simplistic, and screening collections have not necessarily been well suited to identifying leads in new areas. Despite the relative shortage of high-quality tool molecules in a number of cases, there is an emerging, and increasingly substantial, body of evidence associating many as yet "undrugged" receptors with a very wide range of diseases. Significant advances in our understanding of receptor pharmacology and technical advances in screening, protein X-ray crystallography, and ligand design methods are paving the way for new successes in the area. Exploitation of allosteric mechanisms; alternative signaling pathways such as G12/13, Gβγ, and β-arrestin; the discovery of "biased" ligands; and the emergence of GPCR-protein complexes as potential drug targets offer scope for new and much improved drugs.

show abstract

4‐Acylamino‐ and 4‐Ureidobenzamides as Melanin‐Concentrating Hormone (MCH) Receptor 1 Antagonists

Cited by 6 publications

References 1 publication

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

A chemogenomic analysis of the transmembrane binding cavity of human G‐protein‐coupled receptors

Definition of the G Protein-Coupled Receptor Transmembrane Bundle Binding Pocket and Calculation of Receptor Similarities for Drug Design

Are GPCRs Still a Source of New Targets?

Contact Info

Product

Resources

About