Novel Triazole‐Tethered Derivatives of Nor‐codeine: Synthesis, Radioligand Binding Assay, Docking Study and Evaluation of Their Analgesic Properties

• Published in: ChemistrySelect (Weinheim) Vol. 5; no. 46; pp. 14753 - 14758
• Main Authors: Gharehnaghadeh, Saman, Salehi, Peyman, Bararjanian, Morteza, Pecio, Łukasz, Babanezhad‐Harikandei, Kosar, Khoramjouy, Mona, Shahhosseini, Soraya, Faizi, Mehrdad
• Format: Journal Article
• Language: English
• Published: 11.12.2020
• Subjects: 1,2,3-Triazole; Click chemistry; Codeine; Radioligand binding assay; Tail-flick test
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202003684

A series of novel 1,4‐disubstituted 1,2,3‐triazole derivatives of nor‐codeine were synthesized by N‐demethylation of codeine by a new procedure followed by propargylation of nitrogen and alkyne‐azide cycloaddition reaction. Affinities of all compounds to Mu opioid receptors were evaluated by in vitro radioligand binding assay method. Seven compounds out of all eighteen novel products were selected for in vivo analgesic tail flick test. Most of the synthesized compounds showed promising results in which 3‐((1‐(2‐hydroxy‐3‐phenoxypropyl)‐1H‐1,2,3,–triazol‐4‐yl)methyl)‐9‐methoxy‐2,3,4,4a,7,7a hexahydro‐1H‐4,12‐methanobenzofuro[3,2‐e]isoquinolin‐7‐ol (16 e) with an ED50 of 8.68 mg/kg revealed considerable analgesic activity even better than codeine (9.55 mg/kg) as a commercial drug. Also, docking studies were made on Mu opioid receptor (BU72) which showed good agreement with experimental data. The mentioned compound had the highest docking scores of −10.84 and −9.90 kcal/mol for R and S diastereomers, respectively. New 1,4‐disubstituted 1,2,3‐triazole derivatives of nor‐codeine were prepared, in vivo and in vitro analgesic activity of synthesized compounds were evaluated by radioligand binding assay and tail flick test respectively, finally experimental data were compared to docking studies on Mu opioid receptor (BU72). Most of the synthesized compounds showed promising results in which compound 3‐((1‐(2‐hydroxy‐3‐phenoxypropyl)‐1H‐1,2,3,–triazol‐4‐yl)methyl)‐9‐methoxy‐2,3,4,4a,7,7a hexahydro‐1H‐4,12‐methanobenzofuro[3,2‐e]isoquinolin‐7‐ol with an ED50 of 8.68 mg/kg revealed considerable analgesic activity even more than codeine (9.55 mg/kg) as a commercial drug.