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Triarylmethanes, a New Class of Cx50 Inhibitors

The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design o...

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Autores principales: Bodendiek, Silke B., Rubinos, Clio, Trelles, Maria Pilar, Coleman, Nichole, Jenkins, David Paul, Wulff, Heike, Srinivas, Miduturu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Research Foundation 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368247/
https://www.ncbi.nlm.nih.gov/pubmed/22685432
http://dx.doi.org/10.3389/fphar.2012.00106
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author Bodendiek, Silke B.
Rubinos, Clio
Trelles, Maria Pilar
Coleman, Nichole
Jenkins, David Paul
Wulff, Heike
Srinivas, Miduturu
author_facet Bodendiek, Silke B.
Rubinos, Clio
Trelles, Maria Pilar
Coleman, Nichole
Jenkins, David Paul
Wulff, Heike
Srinivas, Miduturu
author_sort Bodendiek, Silke B.
collection PubMed
description The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design of high affinity inhibitors of other ion channels, to identify a specific inhibitor for channels formed by Cx50, a connexin subtype that is primarily expressed in the lens. We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds. The triarlymethane (TRAM) clotrimazole was the most potent Cx50 inhibitor and we therefore used it as a template to explore the structure activity relationship (SAR) of the TRAMs for Cx50 inhibition. We describe the design of T122 (N-[(2-methoxyphenyl)diphenylmethyl]-1,3-thiazol-2-amine) and T136 (N-[(2-iodophenyl)diphenylmethyl]-1,3-thiazol-2-amine), which inhibit Cx50 with IC(50)s of 1.2 and 2.4 μM. Both compounds exhibit at least 10-fold selectivity over other connexins as well as major neuronal and cardiac voltage-gated K(+) and Na(+) channels. The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel. Both T122 and T136 selectively inhibited Cx50 GJ channels in lens epithelial cells, suggesting that they could be used to further explore the role of Cx50 in the lens. In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes.
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spelling pubmed-33682472012-06-08 Triarylmethanes, a New Class of Cx50 Inhibitors Bodendiek, Silke B. Rubinos, Clio Trelles, Maria Pilar Coleman, Nichole Jenkins, David Paul Wulff, Heike Srinivas, Miduturu Front Pharmacol Pharmacology The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design of high affinity inhibitors of other ion channels, to identify a specific inhibitor for channels formed by Cx50, a connexin subtype that is primarily expressed in the lens. We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds. The triarlymethane (TRAM) clotrimazole was the most potent Cx50 inhibitor and we therefore used it as a template to explore the structure activity relationship (SAR) of the TRAMs for Cx50 inhibition. We describe the design of T122 (N-[(2-methoxyphenyl)diphenylmethyl]-1,3-thiazol-2-amine) and T136 (N-[(2-iodophenyl)diphenylmethyl]-1,3-thiazol-2-amine), which inhibit Cx50 with IC(50)s of 1.2 and 2.4 μM. Both compounds exhibit at least 10-fold selectivity over other connexins as well as major neuronal and cardiac voltage-gated K(+) and Na(+) channels. The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel. Both T122 and T136 selectively inhibited Cx50 GJ channels in lens epithelial cells, suggesting that they could be used to further explore the role of Cx50 in the lens. In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes. Frontiers Research Foundation 2012-06-06 /pmc/articles/PMC3368247/ /pubmed/22685432 http://dx.doi.org/10.3389/fphar.2012.00106 Text en Copyright © 2012 Bodendiek, Rubinos, Trelles, Coleman, Jenkins, Wulff and Srinivas. http://www.frontiersin.org/licenseagreement This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
spellingShingle Pharmacology
Bodendiek, Silke B.
Rubinos, Clio
Trelles, Maria Pilar
Coleman, Nichole
Jenkins, David Paul
Wulff, Heike
Srinivas, Miduturu
Triarylmethanes, a New Class of Cx50 Inhibitors
title Triarylmethanes, a New Class of Cx50 Inhibitors
title_full Triarylmethanes, a New Class of Cx50 Inhibitors
title_fullStr Triarylmethanes, a New Class of Cx50 Inhibitors
title_full_unstemmed Triarylmethanes, a New Class of Cx50 Inhibitors
title_short Triarylmethanes, a New Class of Cx50 Inhibitors
title_sort triarylmethanes, a new class of cx50 inhibitors
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368247/
https://www.ncbi.nlm.nih.gov/pubmed/22685432
http://dx.doi.org/10.3389/fphar.2012.00106
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