Preliminary in vitro permeability, cytotoxicity and cardiotoxicity evaluation of triazole-quinuclidine T6

Abstract

© Faculty of Pharmacy, Mahidol University (Thailand) 2019. The permeability and safety of two lead compounds, (R)-T6 and (S)-T6, which are selective nicotinic acetylcholine receptor (nAChR) ligands for α7 nAChR and α3β4 nAChR, respectively, were evaluated in vitro to provide support to move on to preclinical studies. The α7 nAChR is well recognized as a drug target for neurodegenerative diseases while that of α3β4 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 2.47×10-6 and 8.99×10-6 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 μM, respectively. For cardiac-safety test, the effect on human ether-a-go-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.