Publication: Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds
Issued Date
2016-10-13
Resource Type
ISSN
19485875
Other identifier(s)
2-s2.0-84991574459
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Medicinal Chemistry Letters. Vol.7, No.10 (2016), 890-895
Suggested Citation
Jiradanai Sarasamkan, Matthias Scheunemann, Nattayaporn Apaijai, Siripong Palee, Warisara Parichatikanond, Kuntarat Arunrungvichian, Steffen Fischer, Siriporn Chattipakorn, Winnie Deuther-Conrad, Gerrit Schüürmann, Peter Brust, Opa Vajragupta Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds. ACS Medicinal Chemistry Letters. Vol.7, No.10 (2016), 890-895. doi:10.1021/acsmedchemlett.6b00146 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/42964
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds
Abstract
© 2016 American Chemical Society. The novel quinuclidine anti-1,2,3-triazole derivatives T1-T6 were designed based on the structure of QND8. The binding studies revealed that the stereochemistry at the C3 position of the quinuclidine scaffold plays an important role in the nAChR subtype selectivity. Whereas the (R)-enantiomers are selective to α7 over α4β2 (by factors of 44-225) and to a smaller degree over α3β4 (3-33), their (S)-counterparts prefer α3β4 over α4β2 (62-237) as well as over α7 (5-294). The (R)-derivatives were highly selective to α7 over α3β4 subtypes compared to (RS)- and (R)-QND8. The (S)-enantiomers are 5-10 times more selective to α4β2 than their (R) forms. The overall strongest affinity is observed for the (S)-enantiomer binding to α3β4 (Ki, 2.25-19.5 nM) followed by their (R)-counterpart binding to α7 (Ki, 22.5-117 nM), with a significantly weaker (S)-enantiomer binding to α4β2 (Ki, 414-1980 nM) still above the very weak respective (R)-analogue affinity (Ki, 5059-10436 nM).