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

Publication ,  Journal Article
Schwarz, DA; Allen, MM; Petroski, RE; Pomeroy, JE; Heise, CE; Mistry, MS; Selkirk, JV; Nottebaum, LM; Grey, J; Zhang, M; Goodfellow, VS; Maki, RA
Published in: Mol Cell Endocrinol
October 19, 2006

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.

Duke Scholars

Published In

Mol Cell Endocrinol

DOI

ISSN

0303-7207

Publication Date

October 19, 2006

Volume

259

Issue

1-2

Start / End Page

1 / 9

Location

Ireland

Related Subject Headings

  • Somatostatin
  • Receptors, Somatostatin
  • Rats
  • Pyridazines
  • Neurons
  • Models, Biological
  • Hydrophobic and Hydrophilic Interactions
  • Humans
  • Endocrinology & Metabolism
  • Drug Design
 

Citation

APA
Chicago
ICMJE
MLA
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Schwarz, D. A., Allen, M. M., Petroski, R. E., Pomeroy, J. E., Heise, C. E., Mistry, M. S., … Maki, R. A. (2006). Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Mol Cell Endocrinol, 259(1–2), 1–9. https://doi.org/10.1016/j.mce.2006.07.003
Schwarz, David A., Molly M. Allen, Robert E. Petroski, Jordan E. Pomeroy, Christopher E. Heise, Monica S. Mistry, Julie V. Selkirk, et al. “Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function.Mol Cell Endocrinol 259, no. 1–2 (October 19, 2006): 1–9. https://doi.org/10.1016/j.mce.2006.07.003.
Schwarz DA, Allen MM, Petroski RE, Pomeroy JE, Heise CE, Mistry MS, et al. Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Mol Cell Endocrinol. 2006 Oct 19;259(1–2):1–9.
Schwarz, David A., et al. “Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function.Mol Cell Endocrinol, vol. 259, no. 1–2, Oct. 2006, pp. 1–9. Pubmed, doi:10.1016/j.mce.2006.07.003.
Schwarz DA, Allen MM, Petroski RE, Pomeroy JE, Heise CE, Mistry MS, Selkirk JV, Nottebaum LM, Grey J, Zhang M, Goodfellow VS, Maki RA. Manipulation of small-molecule inhibitory kinetics modulates MCH-R1 function. Mol Cell Endocrinol. 2006 Oct 19;259(1–2):1–9.
Journal cover image

Published In

Mol Cell Endocrinol

DOI

ISSN

0303-7207

Publication Date

October 19, 2006

Volume

259

Issue

1-2

Start / End Page

1 / 9

Location

Ireland

Related Subject Headings

  • Somatostatin
  • Receptors, Somatostatin
  • Rats
  • Pyridazines
  • Neurons
  • Models, Biological
  • Hydrophobic and Hydrophilic Interactions
  • Humans
  • Endocrinology & Metabolism
  • Drug Design