[ Pharmaceutical Sciences Asia - ONLINE ]
E-ISSN 2586-8470
[ Journal Abbreviation: Pharm.Sci.Asia ]
Mahidol University Journal of Pharmaceutical Sciences
  FORMER NAME   "Mahidol University Journal of Pharmaceutical Sciences" Published Since 1974


DOI: 10.29090/psa.2019.03.018.0043Pharm Sci Asia 2019; 46(3), 156-162

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

Kuntarat Arunrungvichian1*,Putthiporn Khongkaew1,2,Sununta Panyasang1,Jiradanai Sarasamkan3

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudha Road, Bangkok 10400, Thailand
2 Faculty of Pharmaceutical Science, Burapha University, 169 Long-haad Bangsaen Road, Saensook, Mueng, Chonburi 20131, Thailand
3 National Cyclotron and PET Centre, Chulabhorn Hospital, 54 Kamphaeng Phet 6 Road, Bangkok 10210, Thailand

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

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