Molecular mechanism of action of triazolobenzodiazepinone agonists of the type 1 cholecystokinin receptor. Possible cooperativity across the receptor homodimeric complex

Aditya J Desai, Polo C H Lam, Andrew Orry, Ruben Abagyan, Arthur Christopoulos, Patrick Sexton, Laurence J Miller

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The type 1 cholecystokinin receptor (CCK1R) has multiple physiologic roles relating to nutrient homeostasis, including mediation of postcibal satiety. This effect has been central in efforts to develop agonists of this receptor as part of a program to manage and/or prevent obesity. While a number of small molecule CCK1R agonists have been developed, none have yet been approved for clinical use, based on inadequate efficacy, side effects, or the potential for toxicity. Understanding the molecular details of docking and mechanism of action of these ligands can be helpful in the rational refinement and enhancement of small molecule drug candidates. In the current work, we have defined the mechanism of binding and activity of two triazolobenzodiazepinones, CE-326597 and PF-04756956, which are reported to be full agonist ligands. To achieve this, we utilized receptor binding with a series of allosteric and orthosteric radioligands at structurally related CCK1R and CCK2R, as well as chimeric CCK1R/CCK2R constructs exchanging residues in the allosteric pocket, and assessment of biological activity. These triazolobenzodiazepinones docked within the intramembranous small molecule allosteric ligand pocket, with higher affinity binding to CCK2R than CCK1R, yet with biological activity exclusive to or greatly enhanced at CCK1R. These ligands exhibited cooperativity with benzodiazepine binding across the CCK1R homodimeric complex, resulting in their ability to inhibit only a fraction of the saturable binding of a benzodiazepine radioligand, unlike other small molecule antagonists and agonists of this receptor. This may contribute to the understanding of the unique short duration and reversible gallbladder contraction observed in vivo upon administration of these drugs.
Original languageEnglish
Pages (from-to)9562-9577
Number of pages16
JournalJournal of Medicinal Chemistry
Volume58
Issue number24
DOIs
Publication statusPublished - 2015

Cite this

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title = "Molecular mechanism of action of triazolobenzodiazepinone agonists of the type 1 cholecystokinin receptor. Possible cooperativity across the receptor homodimeric complex",
abstract = "The type 1 cholecystokinin receptor (CCK1R) has multiple physiologic roles relating to nutrient homeostasis, including mediation of postcibal satiety. This effect has been central in efforts to develop agonists of this receptor as part of a program to manage and/or prevent obesity. While a number of small molecule CCK1R agonists have been developed, none have yet been approved for clinical use, based on inadequate efficacy, side effects, or the potential for toxicity. Understanding the molecular details of docking and mechanism of action of these ligands can be helpful in the rational refinement and enhancement of small molecule drug candidates. In the current work, we have defined the mechanism of binding and activity of two triazolobenzodiazepinones, CE-326597 and PF-04756956, which are reported to be full agonist ligands. To achieve this, we utilized receptor binding with a series of allosteric and orthosteric radioligands at structurally related CCK1R and CCK2R, as well as chimeric CCK1R/CCK2R constructs exchanging residues in the allosteric pocket, and assessment of biological activity. These triazolobenzodiazepinones docked within the intramembranous small molecule allosteric ligand pocket, with higher affinity binding to CCK2R than CCK1R, yet with biological activity exclusive to or greatly enhanced at CCK1R. These ligands exhibited cooperativity with benzodiazepine binding across the CCK1R homodimeric complex, resulting in their ability to inhibit only a fraction of the saturable binding of a benzodiazepine radioligand, unlike other small molecule antagonists and agonists of this receptor. This may contribute to the understanding of the unique short duration and reversible gallbladder contraction observed in vivo upon administration of these drugs.",
author = "Desai, {Aditya J} and Lam, {Polo C H} and Andrew Orry and Ruben Abagyan and Arthur Christopoulos and Patrick Sexton and Miller, {Laurence J}",
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journal = "Journal of Medicinal Chemistry",
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Molecular mechanism of action of triazolobenzodiazepinone agonists of the type 1 cholecystokinin receptor. Possible cooperativity across the receptor homodimeric complex. / Desai, Aditya J; Lam, Polo C H; Orry, Andrew; Abagyan, Ruben; Christopoulos, Arthur; Sexton, Patrick; Miller, Laurence J.

In: Journal of Medicinal Chemistry, Vol. 58, No. 24, 2015, p. 9562-9577.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Lam, Polo C H

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AU - Abagyan, Ruben

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AU - Sexton, Patrick

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