Sam R J Hoare
Affiliation: Neurocrine Biosciences
- Binding kinetics redefine the antagonist pharmacology of the corticotropin-releasing factor type 1 receptorBeth A Fleck
Neurocrine Biosciences Inc, San Diego, California, USA
J Pharmacol Exp Ther 341:518-31. 2012..Collectively, these findings demonstrate receptor binding kinetics provide new dimensions for understanding and potentially advancing the pharmacology of CRF₁ receptor antagonists...
- Mechanisms of peptide and nonpeptide ligand binding to Class B G-protein-coupled receptorsSam R J Hoare
Department of Pharmacology Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA
Drug Discov Today 10:417-27. 2005..Here, these mechanisms of peptide and nonpeptide ligand binding are reviewed, then applied in a discussion of the future strategies of drug development for Class B G-protein-coupled receptors...
- Single amino acid residue determinants of non-peptide antagonist binding to the corticotropin-releasing factor1 (CRF1) receptorSam R J Hoare
Department of Discovery Biology, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
Biochem Pharmacol 72:244-55. 2006....
- Peptide ligand binding properties of the corticotropin-releasing factor (CRF) type 2 receptor: pharmacology of endogenously expressed receptors, G-protein-coupling sensitivity and determinants of CRF2 receptor selectivitySam R J Hoare
Department of Pharmacology, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
Peptides 26:457-70. 2005..These findings will be important for identifying the CRF2 receptor in tissues and for developing ligands targeting the receptor, both of which will be useful in identifying the emerging physiological functions of the CRF2 receptor...
- Allosteric ligands for the corticotropin releasing factor type 1 receptor modulate conformational states involved in receptor activationSam R J Hoare
Emerging Technologies Biomedical Research and Innovative Discovery Group, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
Mol Pharmacol 73:1371-80. 2008....
- Conformational states of the corticotropin releasing factor 1 (CRF1) receptor: detection, and pharmacological evaluation by peptide ligandsSam R J Hoare
Department of Pharmacology, Neurocrine Biosciences Inc, 10555 Science Center Dr, San Diego, CA 92121 1102, USA
Peptides 24:1881-97. 2003..This study provides a framework to identify CRF1 receptor conformational states in various receptor preparations...
- Ligand affinity for amino-terminal and juxtamembrane domains of the corticotropin releasing factor type I receptor: regulation by G-protein and nonpeptide antagonistsSam R J Hoare
Department of Pharmacology, Neurocrine Biosciences Inc, San Diego, California 92121 1102, USA
Biochemistry 43:3996-4011. 2004..2) Agonist-J-domain interaction is allosterically enhanced by receptor-G-protein interaction and inhibited by nonpeptide antagonist...
- Mechanism of corticotropin-releasing factor type I receptor regulation by nonpeptide antagonistsSam R J Hoare
Department of Pharmacology, Neurocrine Biosciences Inc, San Diego, California, USA
Mol Pharmacol 63:751-65. 2003..Strong inhibition at RG explains the antagonist properties of the compounds...
- Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonistsRaymond S Gross
Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, California 92130, USA
J Med Chem 48:5780-93. 2005..1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo...
- Molecular interactions of nonpeptide agonists and antagonists with the melanocortin-4 receptorBeth A Fleck
Department of Pharmacology, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, California 92130, USA
Biochemistry 44:14494-508. 2005..Furthermore, the strength of interaction with the aromatic pocket, and potentially the acidic pocket, controls the signaling efficacy of the ligand...
- Kinetics of nonpeptide antagonist binding to the human gonadotropin-releasing hormone receptor: Implications for structure-activity relationships and insurmountable antagonismSusan K Sullivan
Department of Pharmacology and Lead Discovery, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
Biochem Pharmacol 72:838-49. 2006..These findings are of importance for the future definition of nonpeptide ligand SAR and for the identification of potentially useful slowly dissociating antagonists for the GnRH receptor...
- Distinct conformations of the corticotropin releasing factor type 1 receptor adopted following agonist and antagonist binding are differentially regulatedStephen J Perry
Department of Molecular Biology, Neurocrine Biosciences Inc, San Diego, California 92130, USA
J Biol Chem 280:11560-8. 2005..These data demonstrate that agonists and antagonists for CRF1 receptors promote distinct conformations, which are then differentially regulated...
- Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic propertiesJohn E Tellew
Department of Medicinal Chemistry, Neurocrine Biosciences, San Diego, CA 92130, USA
Bioorg Med Chem Lett 20:7259-64. 2010..Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay...
- Analytical method for simultaneously measuring ex vivo drug receptor occupancy and dissociation rate: application to (R)-dimethindene occupancy of central histamine H1 receptorsSiobhan Malany
Division of Emerging New Technologies, Neurocrine Biosciences, San Diego, California, USA
J Recept Signal Transduct Res 29:84-93. 2009..Data described by the method may be analyzed with commercially available software. Suggested fitting procedures are given in the appendix...
- A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated miceJoseph Pontillo
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
Bioorg Med Chem Lett 15:2541-6. 2005..2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration...
- Phenylguanidines as selective nonpeptide melanocortin-5 receptor antagonistsChen Chen
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
J Med Chem 47:4083-8. 2004..Compound 10 had a K(i) value of 2.1 nM in the binding assay and an IC(50) of 72 nM in the functional assay. Some analogues such as 13 from this series possessed weak agonist activity at the human MC4 receptor...
- The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonistStacy Markison
Department of Pediatrics, Mailcode CDRCP, 707 Southwest Gaines Road, Portland, Oregon 97239, USA
Endocrinology 146:2766-73. 2005..These data clearly demonstrate the potential of small molecule MC4-R antagonists in the treatment of cachexia and underscore the importance of melanocortin signaling in the development of this metabolic disorder...
- Functional selectivity of melanocortin 4 receptor peptide and nonpeptide agonists: evidence for ligand-specific conformational statesSarah A Nickolls
Neurocrine Biosciences Inc, Sandwich, Kent, UK
J Pharmacol Exp Ther 313:1281-8. 2005..These findings demonstrate an important difference in activation and internalization of the MC4 receptor by nonpeptide versus peptide agonists and provides evidence of agonist-specific conformational states...
- Specificity and stability of a new PTH1 receptor antagonist, mouse TIP(7-39)Sam R J Hoare
Unit on Cell Biology, National Institute of Mental Health, Room 3D06, Bld 36, 36 Convent Drive, Bethesda, MD 20892 4092, USA
Peptides 23:989-98. 2002..6 min (92%), and t(1/2)=21 min (8%)). Loss of unlabeled mTIP(7-39) (250 microg/kg i.v.) receptor binding was similar. mTIP(7-39)'s high-affinity should facilitate animal evaluation of effects of PTH1 receptor antagonism...