15741-80-7Relevant articles and documents
Identification of a Potent Tryptophan-Based TRPM8 Antagonist with in Vivo Analgesic Activity
Bertamino, Alessia,Iraci, Nunzio,Ostacolo, Carmine,Ambrosino, Paolo,Musella, Simona,Di Sarno, Veronica,Ciaglia, Tania,Pepe, Giacomo,Sala, Marina,Soldovieri, Maria Virginia,Mosca, Ilaria,Gonzalez-Rodriguez, Sara,Fernandez-Carvajal, Asia,Ferrer-Montiel, Antonio,Novellino, Ettore,Taglialatela, Maurizio,Campiglia, Pietro,Gomez-Monterrey, Isabel
, p. 6140 - 6152 (2018/07/05)
TRPM8 has been implicated in nociception and pain and is currently regarded as an attractive target for the pharmacological treatment of neuropathic pain syndromes. A series of analogues of N,N′-dibenzyl tryptamine 1, a potent TRPM8 antagonist, was prepared and screened using a fluorescence-based in vitro assay based on menthol-evoked calcium influx in TRPM8 stably transfected HEK293 cells. The tryptophan derivative 14 was identified as a potent (IC50 0.2 ± 0.2 nM) and selective TRPM8 antagonist. In vivo, 14 showed significant target coverage in both an icilin-induced WDS (at 1-30 mg/kg s.c.) and oxaliplatin-induced cold allodynia (at 0.1-1 μg s.c.) mice models. Molecular modeling studies identified the putative binding mode of these antagonists, suggesting that they could influence an interaction network between the S1-4 transmembrane segments and the TRP domains of the channel subunits. The tryptophan moiety provides a new pharmacophoric scaffold for the design of highly potent modulators of TRPM8-mediated pain.
Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators
Bertamino, Alessia,Ostacolo, Carmine,Ambrosino, Paolo,Musella, Simona,Di Sarno, Veronica,Ciaglia, Tania,Soldovieri, Maria Virginia,Iraci, Nunzio,Fernandez Carvajal, Asia,De La Torre-Martinez, Roberto,Ferrer-Montiel, Antonio,Gonzalez Muniz, Rosario,Novellino, Ettore,Taglialatela, Maurizio,Campiglia, Pietro,Gomez-Monterrey, Isabel
, p. 2179 - 2191 (2016/03/25)
Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl)ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl)ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40 ± 4 μM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentration-dependent inhibition of menthol-induced TRPM8 currents (IC50 = 367 ± 24 nM). Molecular modeling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing differences in the binding modes for the agonist and the antagonist.
Total syntheses of enantiomerically enriched R-(+)- And S-(-)-deplancheinef
Sydorenko, Nadiya,Zificsak, Craig A.,Gerasyuto, Aleksey I.,Hsung, Richard P.
, p. 2140 - 2144 (2007/10/03)
Total syntheses of indoloquinolizidine alkaloid (±)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids. The Royal Society of Chemistry 2005.
