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Identification of the atypical L-type Ca2+ channel blocker diltiazem and its metabolites as ghrelin receptor agonists

Ma, Jian Nong ; Schiffer, Hans H. ; Knapp, Anne E. ; Wang, Jean ; Wong, Kenneth K. ; Currier, Erika A. ; Owens, Michelle ; Nash, Norman R. ; Gardell, Luis R. and Brann, Mark R. , et al. (2007) In Molecular Pharmacology 72(2). p.380-386
Abstract

Using a high-throughput functional screen, the atypical L-type Ca 2+ channel blocker diltiazem was discovered to be an agonist at the human ghrelin (GHSR1a) receptor. In cellular proliferation, Ca2+ mobilization, and bioluminescence resonance energy transfer (BRET-2) assays, diltiazem was a partial agonist at GHSR1a receptors, with 50 to 80% relative efficacy compared with the GHSR1a peptide agonist GHRP-6, and high nanomolar to low micromolar potency, depending upon the assay. Seven of the known primary metabolites of diltiazem were synthesized, and three of them (MA, M1, and M2) were more efficacious and/or more potent than diltiazem at GHSR1a receptors, with a rank order of... (More)

Using a high-throughput functional screen, the atypical L-type Ca 2+ channel blocker diltiazem was discovered to be an agonist at the human ghrelin (GHSR1a) receptor. In cellular proliferation, Ca2+ mobilization, and bioluminescence resonance energy transfer (BRET-2) assays, diltiazem was a partial agonist at GHSR1a receptors, with 50 to 80% relative efficacy compared with the GHSR1a peptide agonist GHRP-6, and high nanomolar to low micromolar potency, depending upon the assay. Seven of the known primary metabolites of diltiazem were synthesized, and three of them (MA, M1, and M2) were more efficacious and/or more potent than diltiazem at GHSR1a receptors, with a rank order of agonist activity of M 2 > M1 > MA > diltiazem, whereas M4 and M6 metabolites displayed weak agonist activity, and the M8 and M9 metabolites were inactive. Binding affinities of diltiazem and these metabolites to GHSR1a receptors followed a similar rank order. In vivo tests showed that diltiazem and M2 each stimulated growth hormone release in male Sprague-Dawley neonatal rats, although to a lesser degree than GHRP-6. Thus, diltiazem and chemical analogs of diltiazem represent a new class of GHSR1a receptor agonists. The possible contributions of GHSR1a receptor activation to the clinical actions of diltiazem are discussed in the context of the known beneficial cardiovascular effects of ghrelin.

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type
Contribution to journal
publication status
published
subject
in
Molecular Pharmacology
volume
72
issue
2
pages
380 - 386
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • scopus:34547142774
  • pmid:17475811
ISSN
0026-895X
DOI
10.1124/mol.107.034298
language
English
LU publication?
no
id
0d8605e5-9603-4b81-b39c-5b8ac4570f43
date added to LUP
2019-10-02 10:27:10
date last changed
2020-01-13 02:26:13
@article{0d8605e5-9603-4b81-b39c-5b8ac4570f43,
  abstract     = {<p>Using a high-throughput functional screen, the atypical L-type Ca <sup>2+</sup> channel blocker diltiazem was discovered to be an agonist at the human ghrelin (GHSR1a) receptor. In cellular proliferation, Ca<sup>2+</sup> mobilization, and bioluminescence resonance energy transfer (BRET-2) assays, diltiazem was a partial agonist at GHSR1a receptors, with 50 to 80% relative efficacy compared with the GHSR1a peptide agonist GHRP-6, and high nanomolar to low micromolar potency, depending upon the assay. Seven of the known primary metabolites of diltiazem were synthesized, and three of them (M<sub>A</sub>, M<sub>1</sub>, and M<sub>2</sub>) were more efficacious and/or more potent than diltiazem at GHSR1a receptors, with a rank order of agonist activity of M <sub>2</sub> &gt; M<sub>1</sub> &gt; M<sub>A</sub> &gt; diltiazem, whereas M<sub>4</sub> and M<sub>6</sub> metabolites displayed weak agonist activity, and the M<sub>8</sub> and M<sub>9</sub> metabolites were inactive. Binding affinities of diltiazem and these metabolites to GHSR1a receptors followed a similar rank order. In vivo tests showed that diltiazem and M<sub>2</sub> each stimulated growth hormone release in male Sprague-Dawley neonatal rats, although to a lesser degree than GHRP-6. Thus, diltiazem and chemical analogs of diltiazem represent a new class of GHSR1a receptor agonists. The possible contributions of GHSR1a receptor activation to the clinical actions of diltiazem are discussed in the context of the known beneficial cardiovascular effects of ghrelin.</p>},
  author       = {Ma, Jian Nong and Schiffer, Hans H. and Knapp, Anne E. and Wang, Jean and Wong, Kenneth K. and Currier, Erika A. and Owens, Michelle and Nash, Norman R. and Gardell, Luis R. and Brann, Mark R. and Olsson, Roger and Burstein, Ethan S.},
  issn         = {0026-895X},
  language     = {eng},
  month        = {08},
  number       = {2},
  pages        = {380--386},
  publisher    = {American Society for Pharmacology and Experimental Therapeutics},
  series       = {Molecular Pharmacology},
  title        = {Identification of the atypical L-type Ca<sup>2+</sup> channel blocker diltiazem and its metabolites as ghrelin receptor agonists},
  url          = {http://dx.doi.org/10.1124/mol.107.034298},
  doi          = {10.1124/mol.107.034298},
  volume       = {72},
  year         = {2007},
}