Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function.

Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Abstract Text:

David A Schwarz,Molly M Allen,Robert E Petroski,Jordan E Pomeroy,Christopher E Heise,Monica S Mistry,Julie V Selkirk,Lisa M Nottebaum,Jonathan Grey,Mingzhu Zhang,Val S Goodfellow,Richard A Maki,

The capacity of novel benzopyridazinone-based antagonists to inhibit MCH-R1 function, relative to their affinity for the receptor, has been investigated. Three compounds that differ by the addition of either a chlorine atom, or trifluoromethyl group, have nearly identical receptor affinities; however their abilities to inhibit receptor elicited signaling events, measured as a function of time, are dramatically altered. Both the chlorinated and trifluoromethyl modified compounds have a very slow on-rate to maximal functional inhibition relative to the unmodified base compound. A similar impact on inhibitory capacity can be achieved by modifying the side-chain composition at position 2.53 of the receptor; replacement of the native phenylalanine with alanine significantly reduces the amount of time required by the chlorinated compound to attain maximal functional inhibition. The primary attribute responsible for this alteration in inhibitory capacity appears to be the overall bulk of the amino acid at this position-substitution of the similarly sized amino acids leucine and tyrosine results in phenotypes that are indistinguishable from the wild type receptor. Finally, the impact of these differential inhibitory kinetics has been examined in cultured rat neurons by measuring the ability of the compounds to reverse MCH mediated inhibition of calcium currents. As observed using the cell expression models, the chlorinated compound has a diminished capacity to interfere with receptor function. Collectively, these data suggest that differential inhibitory on rates between a small-molecule antagonist and its target receptor can impact the ability of the compound to modify the biological response(s) elicited by the receptor.

Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Publishing Authors By Initials

DA Schwarz,MM Allen,RE Petroski,JE Pomeroy,CE Heise,MS Mistry,JV Selkirk,LM Nottebaum,J Grey,M Zhang,VS Goodfellow,RA Maki,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Molecular and cellular endocrinology

VOLUME: 259

Page Numbers: 1-9

Journal Abbreviation:

ISSN: 0303-7207

DAY: 20

MONTH: 09

YEAR: 2006

Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7500844

Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function.

AFFILIATION: Neurocrine Biosciences, Inc., Department of Molecular Biology, 12790 El Camino Real, San Diego, CA 92130, USA. dschwarz@neurocrine.com

Country: Ireland

AGENCY:

GRANT:

ACRONYM:

MEDLINETA: Mol Cell Endocrinol

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function Related Publications

• A novel homogeneous bioluminescence resonance energy transfer element for biomolecular detection with CCD camera or CMOS device.
• A retrospective analysis of vinorelbine chemotherapy for patients with previously treated soft-tissue sarcomas.
• An in vitro comparison of bacterial leakage of three common restorative materials used as an intracoronal barrier.
• Brox, a novel farnesylated Bro1 domain-containing protein that associates with charged multivesicular body protein 4 (CHMP4).
• Calphobindins (placental annexins) inhibit protein kinase C.
• Can jua be a weapon in combating oral diseases?
• Characterization of recombinant mouse epidermal-type transglutaminase (TGase 3): regulation of its activity by proteolysis and guanine nucleotides.
• Cohort study of the pathogenesis and molecular epidemiology of catheter-related bloodstream infection in neonates with peripherally inserted central venous catheters *.
• Development of a Multi-channel, Portable Optical Topography System.
• Effects of bisphosphonate on the mandible of rats in the growing phase with steroid-induced osteoporosis.
• Four types of calpastatin isoforms with distinct amino-terminal sequences are specified by alternative first exons and differentially expressed in mouse tissues.
• Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future.
• Isolation and characterization of an anticoagulant protein from human placenta.
• Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function.
• Measuring balance in the elderly: validation of an instrument.
• Nanowire-transistor based ultra-sensitive DNA methylation detection.
• P53 and p73 differ in their ability to inhibit glucocorticoid receptor (GR) transcriptional activity.
• Perioperative chemotherapy in patients undergoing pulmonary resection for metastatic soft-tissue sarcoma of the extremity : a retrospective analysis.
• Recent advances in therapy for gastrointestinal stromal tumors.
• Requirement of different subdomains of calpastatin for calpain inhibition and for binding to calmodulin-like domains.
• Reversible CT changes in uremic encephalopathy.
• Sex difference in cognitive response to antipsychotic treatment in first episode schizophrenia.
• Small cauda equina neurinoma detected by MR imaging.
• Structure and expression of cDNA for calphobindin II, a human placental coagulation inhibitor.
• Structure and properties of calphobindin II, an anticoagulant protein from human placenta.
• THE EFFECTS OF VENTILATION ON THE ABSORPTION AND ELIMINATION OF INHALATION ANAESTHETICS.
• The complete amino acid sequence of rice bran trypsin inhibitor.
• The dnaE173 mutator mutation confers on the alpha subunit of Escherichia coli DNA polymerase III a capacity for highly processive DNA synthesis and stable binding to primer/template DNA.
• The penta-EF-hand protein ALG-2 interacts with a region containing PxY repeats in Alix/AIP1, which is required for the subcellular punctate distribution of the amino-terminal truncation form of Alix/AIP1.
• Transition from a chain-collapse process to a chain-aggregation process of poly(methyl methacrylate) in a mixed solvent.