Issue 10, 2022

N-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1

Abstract

Transient receptor potential cation channel subfamily V member 1 (TRPV1)-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist. To avoid amide–iminol tautomerization, structurally supported N-methylated amides (i.e., 3-alkoxy-substitued N-meythylamide derivatives of SB366791) were evaluated using a Ca2+ influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. The antagonistic activities of N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide (2) (RLC-TV1004) and N-{3-(3-fluoropropoxy)phenyl}-N-methyl-4-chlorocinnamamide (4) (RLC-TV1006) were found to be approximately three-fold higher (IC50: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC50: 3.7 μM). These results will help reinvigorate the potential of SB366791 in medicinal chemistry applications. The 3-methoxy and 3-fluoroalkoxy substituents were used to obtain radioactive [11C]methoxy- or [18F]fluoroalkoxy-incorporated tracers for in vivo positron emission tomography (PET). Using the 11C- or 18F-labeled derivatives, explorative PET imaging trials were performed in rats.

Graphical abstract: N-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1

Supplementary files

Article information

Article type
Research Article
Submitted
25 May 2022
Accepted
27 Aug 2022
First published
06 Sep 2022

RSC Med. Chem., 2022,13, 1197-1204

N-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1

T. Kida, N. Takahashi, M. X. Mori, J. H. Sun, H. Oota, K. Nishino, T. Okauchi, Y. Ochi, D. Kano, U. Tateishi, Y. Watanabe, Y. Cui, Y. Mori and H. Doi, RSC Med. Chem., 2022, 13, 1197 DOI: 10.1039/D2MD00158F

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