Volume 46, No. 03, Month JULY, Year 2019, Pages 156 - 162

Preliminary in vitro permeability, cytotoxicity and cardiotoxicity evaluation of triazole-quinuclidine t6

Kuntarat Arunrungvichian, Putthiporn Khongkaew, Sununta Panyasang, Jiradanai Sarasamkan

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The permeability and safety of two lead compounds, (R)- T6 and (S)-T6, which are selective nicotinic acetylcholine receptor (nAChR) ligands for ?7 nAChR and ?3?4 nAChR, respectively, were evaluated in vitro to provide support to move on to preclinical studies. The ?7 nAChR is well recognized as a drug target for neurodegenerative diseases while that of ?3?4 nAChR is for drug addiction. The permeability of (R)-T6 and (S)-T6 assessed by parallel artificial membrane permeability assay (PAMPA) indicated high human oral absorption with effective permeability (Pe) of 2.47x10-6 and 8.99x10-6 cm/s, respectively. The cytotoxicity and the cardiotoxicity were determined to assess the safety of (R)-T6 and (S)-T6. The cytotoxic IC50 values of (R)-T6 and (S)-T6 on normal HEK 293 cells obtained by MTT assays were 24.98 and 90.93 ?M, respectively. For cardiac-safety test, the effect on human ether-ago-go-related gene (hERG) potassium channels was determined by fluorescence polarization-based assay, the result suggested that (R)- T6 and (S)-T6 bind to hERG potassium channel but in the same level with the common drugs such as haloperidol and thioridazine. Collectively, (R)-T6 and (S)-T6 exhibited favorable permeability and acceptable safety profile. These preliminary data support the safety and suitability of the (R)-T6 and (S)-T6 to proceed to preclinical animal studies.


T6; Cytotoxicity; Cardiotoxicity; Permeability


Published by : Faculty of Pharmacy, Mahidol University
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