title: Synthesis and structure-activity relationship study of a new series of selective σ(1) receptor ligands for the treatment of pain: 4-aminotriazoles.
abstract: The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ1 receptor (σ1R) ligands are reported. The compounds were prepared using a 4-5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ1R, and the selectivity over the σ2R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ1R potency a minimum lipophilicity was required, while limiting to a defined range of cLogP avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.
authors: Drug Discovery and Preclinical Development, Esteve , Baldiri Reixach, 4-8, 08028 Barcelona, Spain.
authors: José Luis
authors: JL
authors: Díaz
authors: Ute
authors: U
authors: Christmann
authors: Ariadna
authors: A
authors: Fernández
authors: Antoni
authors: A
authors: Torrens
authors: Adriana
authors: A
authors: Port
authors: Rosalia
authors: R
authors: Pascual
authors: Inés
authors: I
authors: Álvarez
authors: Javier
authors: J
authors: Burgueño
authors: Xavier
authors: X
authors: Monroy
authors: Ana
authors: A
authors: Montero
authors: Ariadna
authors: A
authors: Balada
authors: José Miguel
authors: JM
authors: Vela
authors: Carmen
authors: C
authors: Almansa
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology*; D059226:Nociceptive Pain / Q000188:drug therapy*; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D000097605:Sigma-1 Receptor
chemical_list: D000700:Analgesics; D051638:Ether-A-Go-Go Potassium Channels; D009025:Morpholines; D017480:Receptors, sigma; D014230:Triazoles; D000097605:Sigma-1 Receptor; C000598575:1-(3,4-dichlorobenzyl)-N-(2-morpholinoethyl)-1H-1,2,3-triazol-4-amine