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Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor

As part of an ongoing effort to develop a drug targeting the type 1 cholecystokinin receptor (CCK1R) to help prevent and/or treat obesity, we recently performed a high throughput screening effort of small molecules seeking candidates that enhanced the action of the natural agonist, CCK, thus acting...

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Autores principales: Dengler, Daniela G., Harikumar, Kaleeckal G., Yen, Alice, Sergienko, Eduard A., Miller, Laurence J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964746/
https://www.ncbi.nlm.nih.gov/pubmed/36837653
http://dx.doi.org/10.3390/membranes13020150
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author Dengler, Daniela G.
Harikumar, Kaleeckal G.
Yen, Alice
Sergienko, Eduard A.
Miller, Laurence J.
author_facet Dengler, Daniela G.
Harikumar, Kaleeckal G.
Yen, Alice
Sergienko, Eduard A.
Miller, Laurence J.
author_sort Dengler, Daniela G.
collection PubMed
description As part of an ongoing effort to develop a drug targeting the type 1 cholecystokinin receptor (CCK1R) to help prevent and/or treat obesity, we recently performed a high throughput screening effort of small molecules seeking candidates that enhanced the action of the natural agonist, CCK, thus acting as positive allosteric modulators without exhibiting intrinsic agonist action. Such probes would be expected to act in a temporally finite way to enhance CCK action to induce satiety during and after a meal and potentially even modulate activity at the CCK1R in a high cholesterol environment present in some obese patients. The current work focuses on the best scaffold, representing tetracyclic molecules identified through high throughput screening we previously reported. Extensive characterization of the two top “hits” from the previous effort demonstrated them to fulfill the desired pharmacologic profile. We undertook analog-by-catalog expansion of this scaffold using 65 commercially available analogs. In this effort, we were able to eliminate an off-target effect observed for this scaffold while retaining its activity as a positive allosteric modulator of CCK1R in both normal and high cholesterol membrane environments. These insights should be useful in the rational medicinal chemical enhancement of this scaffold and in the future development of candidates to advance to pre-clinical proof-of-concept and to clinical trials.
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spelling pubmed-99647462023-02-26 Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor Dengler, Daniela G. Harikumar, Kaleeckal G. Yen, Alice Sergienko, Eduard A. Miller, Laurence J. Membranes (Basel) Article As part of an ongoing effort to develop a drug targeting the type 1 cholecystokinin receptor (CCK1R) to help prevent and/or treat obesity, we recently performed a high throughput screening effort of small molecules seeking candidates that enhanced the action of the natural agonist, CCK, thus acting as positive allosteric modulators without exhibiting intrinsic agonist action. Such probes would be expected to act in a temporally finite way to enhance CCK action to induce satiety during and after a meal and potentially even modulate activity at the CCK1R in a high cholesterol environment present in some obese patients. The current work focuses on the best scaffold, representing tetracyclic molecules identified through high throughput screening we previously reported. Extensive characterization of the two top “hits” from the previous effort demonstrated them to fulfill the desired pharmacologic profile. We undertook analog-by-catalog expansion of this scaffold using 65 commercially available analogs. In this effort, we were able to eliminate an off-target effect observed for this scaffold while retaining its activity as a positive allosteric modulator of CCK1R in both normal and high cholesterol membrane environments. These insights should be useful in the rational medicinal chemical enhancement of this scaffold and in the future development of candidates to advance to pre-clinical proof-of-concept and to clinical trials. MDPI 2023-01-24 /pmc/articles/PMC9964746/ /pubmed/36837653 http://dx.doi.org/10.3390/membranes13020150 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dengler, Daniela G.
Harikumar, Kaleeckal G.
Yen, Alice
Sergienko, Eduard A.
Miller, Laurence J.
Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor
title Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor
title_full Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor
title_fullStr Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor
title_full_unstemmed Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor
title_short Mechanism of Action and Structure–Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor
title_sort mechanism of action and structure–activity relationships of tetracyclic small molecules acting as universal positive allosteric modulators of the cholecystokinin receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964746/
https://www.ncbi.nlm.nih.gov/pubmed/36837653
http://dx.doi.org/10.3390/membranes13020150
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