Roh, Eun Joo Keller, Jason M. Olah, Zoltan Iadarola, Michael J. Jacobson, Kenneth A. 2024-01-20T22:32:46Z 2024-01-20T22:32:46Z 2021-08-31 2008-10-15 0968-0896 https://pubs.kist.re.kr/handle/201004/133056 Vanilloid agonists such as capsaicin activate ion flux through the TRPV1 channel, a heat- and ligand-gated cation channel that transduces painful chemical or thermal stimuli applied to peripheral nerve endings in skin or deep tissues. We have probed the SAR of a variety of 1,4-dihydropyridine (DHP) derivatives as novel 'enhancers' of TRPV1 activity by examining changes in capsaicin-induced elevations in Ca-45(2+)-uptake in either cells ectopically expressing TRPV1 or in cultured dorsal root ganglion (DRG) neurons. The enhancers increased the maximal capsaicin effect on Ca-45(2+)-uptake by typically 2- to 3-fold without producing an action when used alone. The DHP enhancers contained 6-aryl substitution and small alkyl groups at the 1 and 4 positions, and a 3-phenylalkylthioester was tolerated. Levels of free intracellular Ca2+, as measured by calcium imaging, were also increased in DRG neurons when exposed to the combination of capsaicin and the most efficacious enhancer 23 compared to capsaicin alone. Thus, DHPs can modulate TRPV1 channels in a positive fashion. Published by Elsevier Ltd. English PERGAMON-ELSEVIER SCIENCE LTD ADENOSINE RECEPTOR ANTAGONISTS ROOT GANGLION NEURONS VANILLOID RECEPTOR DIRECT PHOSPHORYLATION 3,5-DIACYL-2,4-DIALKYLPYRIDINE DERIVATIVES PLASMA-MEMBRANE SENSORY NEURONS CAPSAICIN PAIN HYPERALGESIA Structure-activity relationships of 1,4-dihydropyridines that act as enhancers of the vanilloid receptor 1 (TRPV1) Article 10.1016/j.bmc.2008.08.048 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.16, no.20, pp.9349 - 9358 BIOORGANIC & MEDICINAL CHEMISTRY 16 20 9349 9358 scie scopus 000259973200032 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article ADENOSINE RECEPTOR ANTAGONISTS ROOT GANGLION NEURONS VANILLOID RECEPTOR DIRECT PHOSPHORYLATION 3,5-DIACYL-2,4-DIALKYLPYRIDINE DERIVATIVES PLASMA-MEMBRANE SENSORY NEURONS CAPSAICIN PAIN HYPERALGESIA ion channel pain receptor capsaicin dorsal root ganglion