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Transient receptor potential vanilloid (TRPV) 4 is involved in signaling pathways specifically mediating pain and inflammation, making it a promising target for the treatment of various painful and inflammatory conditions. However, only one drug candidate targeting TRPV4 has entered the clinical trials. To identify potential TRPV4 inhibitors for drug development, we screened a library of ion channel-modulating compounds using both structure- and ligand-based virtual screening approaches. Since a high-resolution experimental structure of the human TRPV4 (hTRPV4) was not available during this study, we used a comparative model of hTRPV4 for the structure-based screening by molecular docking. The ligand-based virtual screening was performed using the pharmacophoric features of two known TRPV4 antagonists. Five potential hits were selected based on either the binding stability or the pharmacophore match, and their effect on hTRPV4 was tested using a FLIPRtetra assay. All tested compounds inhibited hTRPV4 at 30 µM, with compound Z1213735368 showing an IC50 of 8 µM at a concentration of 10 µM. Furthermore, natural stilbenoids, known to modulate other TRP channels, were evaluated for their hTRPV4 binding and inhibitory potential. The findings provide insight into the structural determinants of hTRPV4 modulation and may facilitate further efforts in developing therapeutic hTRPV4 ligands. [ABSTRACT FROM AUTHOR]

This article discusses the role of transient receptor potential (TRP) channels in pain, itch, and neurogenic inflammation. It highlights the progress made in understanding TRP channels over the past 25 years, including the identification of specific channels involved in sensory perception. The article also explores the question of whether blocking a single TRP channel or multiple channels would be more effective in providing pain relief. Additionally, it discusses the potential of TRP channels as targets for the treatment of migraine, inflammation, and osteoarthritis. The article concludes by emphasizing the need for further research to distinguish between the specific actions of TRP drugs. [Extracted from the article]

Koivisto, Ari, Detlef Siemen, and Jan Nedergaard. Norepinephrine-induced sustained inward current in brown fat cells: [[Alpha].sub.1] -mediated by nonselective cation channels. Am J Physiol Endocrinol Metab 279: E963-E977, 2000.--The nature of the sustained norepinephrine-induced depolarization in brown fat cells was examined by patch-clamp techniques. Norepinephrine (NE) stimulation led to a whole cell current response consisting of two phases: a first inward current, lasting for only 1 min, and a sustained inward current, lasting as long as the adrenergic stimulation was maintained. The nature of the sustained current was here investigated. It could be induced by the [[Alpha].sub.1] -agonist cirazoline but not by the [[Beta].sub.3] -agonist CGP-12177A. Reduction of extracellular [Cl.sup.-] concentration had no effect, but omission of extracellular [Ca.sup.2+] or [Na.sup.+] totally eliminated it. When unstimulated cells were studied in the cell-attached mode, some activity of [approximately equals] 30 pS nonselective cation channels was observed. NE perfusion led to a 10-fold increase in their open probability (from [approximately equals] 0.002 to [approximately equals] 0.017), which persisted as long as the perfusion was maintained. The activation was much stronger with the [[Alpha].sub.1] -agonist phenylephrine than with the [[Beta].sub.3]-agonist CGP-12177A, and with the [Ca.sup.2+] ionophore A-23187 than with the adenylyl cyclase activator forskolin. We conclude that the sustained inward current was due to activation of [approximately equals] 30 pS nonselective cation channels via [[Alpha].sub.1] -adrenergic receptors and that the effect may be mediated via an increase in intracellular free [Ca.sup.2+] concentration. cirazoline; calcium; patch-clamp technique