Journal of Medicinal Chemistry p. 6140 - 6152 (2018)
Update date:2022-08-15
Topics:
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
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.
View Morejintan yufan Medicine Raw materials Co.,Ltd.
Contact:86-519-82808282
Address:6th,Jincheng Huangzhuang
Zibo Jujin Chemical Industry Co., Ltd.(Dongming Jujin Chemical Industry Co., Ltd. )
Contact:+86-533-2975022
Address:No.99 Shanquan Road, Zhangdian District
Nanjing distinctions Medical Technology Co., Ltd.
Contact:+86-15996203785 13914714059
Address:nanjing,jiangsu , China
Lanzhou huibang biological chemical technology Co., LTD
Contact:0931-7843964
Address:NO.2011,Yannan Road,Chengguan,
Contact:021
Address:Pudong
Doi:10.1007/s10886-008-9435-1
(2008)Doi:10.1002/chem.201805604
(2019)Doi:10.1021/ol800908h
(2008)Doi:10.1039/c39860000158
(1986)Doi:10.1021/ol800722a
(2008)Doi:10.1007/s00726-014-1747-6
(2014)