Chemokine receptor antagonists with α1-adrenergic receptor blocker activity

Anthony J. DeSantis; Garrett A. Enten; Xianlong Gao; Matthias Majetschak

doi:10.1515/jbcpp-2020-0523

Article

Chemokine receptor antagonists with α₁-adrenergic receptor blocker activity

Anthony J. DeSantis , Garrett A. Enten , Xianlong Gao and Matthias Majetschak

Published/Copyright: June 21, 2021

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From the journal Journal of Basic and Clinical Physiology and Pharmacology Volume 33 Issue 4

Abstract

Objectives

Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C–C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α₁-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α₁-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles.

Methods

The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α_1b-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1–BX471, BX513, BI639667; CCR2–RS504393, INCB3284; CCR3–SB328437; and CCR4–AZD2098, and C021; CCR5–Maraviroc; CCR10-BI6901. The pan-α₁-adrenoceptor antagonist prazosin was used as control.

Results

Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α_1b-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α₁-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α₁-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine.

Conclusions

Our data suggest that CCR antagonists should be screened for cross-reactivity with α₁-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.

Keywords: drug selectivity; off-target activity; vasodilation

Corresponding author: Matthias Majetschak, Departments of Surgery and Molecular Pharmacology & Physiology, University of South Florida, Tampa, FL, USA, Phone: 001 813 974 7126, E-mail: majetschak@usf.edu

Funding source: National Institute of General Medical Sciences

Award Identifier / Grant number: R01GM139811

Award Identifier / Grant number: 10.13039/100000057

Funding source: National Institute of Allergy and Infectious Diseases 10.13039/100000060

Award Identifier / Grant number: R21AI139827

Acknowledgments

Parts of this research had been accepted for presentation at the 43rd Annual Conference on Shock, Toronto, ON, Canada, June 6–9, 2020, which was canceled due to COVID-19 pandemic, and was published as an abstract in Shock 53(S1): 50–51, 2020.

Research funding: Research reported in this publication was supported by the National Institutes of Health under award numbers NIH R01GM139811 and R21AI139827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: N/A.
Ethical approval: All procedures involving animals were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, 8th Edition, and were approved by the Institutional Animal Care and Use Committee of the University of South Florida.

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Received: 2020-12-22

Accepted: 2021-04-14

Published Online: 2021-06-21

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Articles in the same Issue

https://doi.org/10.1515/jbcpp-2020-0523

Keywords for this article

drug selectivity; off-target activity; vasodilation