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Research ArticleArticle

Identification of the Atypical L-Type Ca2+ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Jian-Nong Ma, Hans H. Schiffer, Anne E. Knapp, Jean Wang, Kenneth K. Wong, Erika A. Currier, Michelle Owens, Norman R. Nash, Luis R. Gardell, Mark R. Brann, Roger Olsson and Ethan S. Burstein
Molecular Pharmacology August 2007, 72 (2) 380-386; DOI: https://doi.org/10.1124/mol.107.034298
Jian-Nong Ma
ACADIA Pharmaceuticals, Inc., San Diego, California
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Hans H. Schiffer
ACADIA Pharmaceuticals, Inc., San Diego, California
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Anne E. Knapp
ACADIA Pharmaceuticals, Inc., San Diego, California
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Jean Wang
ACADIA Pharmaceuticals, Inc., San Diego, California
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Kenneth K. Wong
ACADIA Pharmaceuticals, Inc., San Diego, California
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Erika A. Currier
ACADIA Pharmaceuticals, Inc., San Diego, California
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Michelle Owens
ACADIA Pharmaceuticals, Inc., San Diego, California
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Norman R. Nash
ACADIA Pharmaceuticals, Inc., San Diego, California
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Luis R. Gardell
ACADIA Pharmaceuticals, Inc., San Diego, California
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Mark R. Brann
ACADIA Pharmaceuticals, Inc., San Diego, California
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Roger Olsson
ACADIA Pharmaceuticals, Inc., San Diego, California
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Ethan S. Burstein
ACADIA Pharmaceuticals, Inc., San Diego, California
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Abstract

Using a high-throughput functional screen, the atypical L-type Ca2+ 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 M2 > 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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Molecular Pharmacology: 72 (2)
Molecular Pharmacology
Vol. 72, Issue 2
1 Aug 2007
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Research ArticleArticle

Identification of the Atypical L-Type Ca2+ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Jian-Nong Ma, Hans H. Schiffer, Anne E. Knapp, Jean Wang, Kenneth K. Wong, Erika A. Currier, Michelle Owens, Norman R. Nash, Luis R. Gardell, Mark R. Brann, Roger Olsson and Ethan S. Burstein
Molecular Pharmacology August 1, 2007, 72 (2) 380-386; DOI: https://doi.org/10.1124/mol.107.034298

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Research ArticleArticle

Identification of the Atypical L-Type Ca2+ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

Jian-Nong Ma, Hans H. Schiffer, Anne E. Knapp, Jean Wang, Kenneth K. Wong, Erika A. Currier, Michelle Owens, Norman R. Nash, Luis R. Gardell, Mark R. Brann, Roger Olsson and Ethan S. Burstein
Molecular Pharmacology August 1, 2007, 72 (2) 380-386; DOI: https://doi.org/10.1124/mol.107.034298
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