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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

The Nonpeptide Agonist MK-5046 Functions As an Allosteric Agonist for the Bombesin Receptor Subtype-3

Irene Ramos-Alvarez, Tatiana Iordanskaia, Samuel A. Mantey and Robert T. Jensen
Journal of Pharmacology and Experimental Therapeutics August 2022, 382 (2) 66-78; DOI: https://doi.org/10.1124/jpet.121.001033
Irene Ramos-Alvarez
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Tatiana Iordanskaia
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Samuel A. Mantey
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Robert T. Jensen
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Abstract

Allosteric ligands of various G-protein–coupled receptors are being increasingly described and are providing important advances in the development of ligands with novel selectivity and efficacy. These unusual properties allow expanded opportunities for pharmacologic studies and treatment. Unfortunately, no allosteric ligands are yet described for the bombesin receptor family (BnRs), which are proposed to be involved in numerous physiologic/pathophysiological processes in both the central nervous system and peripheral tissues. In this study, we investigate the possibility that the bombesin receptor subtype-3 (BRS-3) specific nonpeptide receptor agonist MK-5046 [(2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-imidazol-2-yl)propan-2-ol] functions as a BRS-3 allosteric receptor ligand. We find that in BRS-3 cells, MK-5046 only partially inhibits iodine-125 radionuclide (125I)-Bantag-1 [Boc-Phe-His-4-amino-5-cyclohexyl-2,4,5-trideoxypentonyl-Leu-(3-dimethylamino) benzylamide N-methylammonium trifluoroacetate] binding and that both peptide-1 (a universal BnR-agonist) and MK-5046 activate phospholipase C; however, the specific BRS-3 peptide antagonist Bantag-1 inhibits the action of peptide-1 competitively, whereas for MK-5046 the inhibition is noncompetitive and yields a curvilinear Schild plot. Furthermore, MK-5046 shows other allosteric behaviors, including slowing dissociation of the BRS-3 receptor ligand 125I-Bantag-1, dose-inhibition curves being markedly affected by increasing ligand concentration, and MK-5046 leftward shifting the peptide-1 agonist dose-response curve. Lastly, receptor chimeric studies and site-directed mutagenesis provide evidence that MK-5046 and Bantag-1 have different binding sites determining their receptor high affinity/selectivity. These results provide evidence that MK-5046 is functioning as an allosteric agonist at the BRS-3 receptor, which is the first allosteric ligand described for this family of receptors.

SIGNIFICANCE STATEMENT G-protein–coupled receptor allosteric ligands providing higher selectivity, selective efficacy, and safety that cannot be obtained using usual orthosteric receptor-based strategies are being increasingly described, resulting in enhanced usefulness in exploring receptor function and in treatment. No allosteric ligands exist for any of the mammalian bombesin receptor (BnR) family. Here we provide evidence for the first such example of a BnR allosteric ligand by showing that MK-5046, a nonpeptide agonist for bombesin receptor subtype-3, is functioning as an allosteric agonist.

Footnotes

    • Received November 22, 2021.
    • Accepted May 5, 2022.
  • This work was partially supported by intramural funds from National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK053200-29] (to R.T.J.).

  • The authors declare that there are no conflicts of interest with the contents of this article.

  • https://doi.org/10.1124/jpet.121.001033.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

MK-5046, BRS-3 Allosteric Agonist

Irene Ramos-Alvarez, Tatiana Iordanskaia, Samuel A. Mantey and Robert T. Jensen
Journal of Pharmacology and Experimental Therapeutics August 1, 2022, 382 (2) 66-78; DOI: https://doi.org/10.1124/jpet.121.001033

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

MK-5046, BRS-3 Allosteric Agonist

Irene Ramos-Alvarez, Tatiana Iordanskaia, Samuel A. Mantey and Robert T. Jensen
Journal of Pharmacology and Experimental Therapeutics August 1, 2022, 382 (2) 66-78; DOI: https://doi.org/10.1124/jpet.121.001033
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