Combination of a Rapidly Penetrating Agonist and a Slowly Penetrating Antagonist Affords Agonist Action of Limited Duration at the Cellular Level
Larry V. Pearce1, Jihyae Ann2, Peter M. Blumberg1,* and Jeewoo Lee2,*
1Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA
2Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
*E-mail: (Lee J), (Blumberg PM)
Tel: +82-2-880-7846 (Lee J), +1-301-695-8029 (Blumberg PM)
Fax: +82-2-888-0649 (Lee J), +1-301-695-8029 (Blumberg PM)
Received: January 22, 2019; Revised: March 15, 2019; Accepted: March 18, 2019; Published online: July 15, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.
Keywords: TRPV1, Capsaicin, Resiniferatoxin, Vanilloid, Pain, Pharmacodynamics

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