title: Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds.
abstract: The novel quinuclidineanti-1,2,3-triazole derivativesT1-T6were designed based on the structure ofQND8. 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).
authors: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand; Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße15, 04318 Leipzig, Germany; National Cyclotron and PET Centre, Chulabhorn Hospital, 54 Kamphaengphet 6 Road, Bangkok 10210, Thailand.
authors: Jiradanai
authors: J
authors: Sarasamkan
authors: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf , Permoserstraße15, 04318 Leipzig, Germany.
authors: Matthias
authors: M
authors: Scheunemann
authors: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University , Chiang Mai 50200, Thailand.
authors: Nattayaporn
authors: N
authors: Apaijai
authors: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University , Chiang Mai 50200, Thailand.
authors: Siripong
authors: S
authors: Palee
authors: Department of Pharmacology, Faculty of Pharmacy, Mahidol University , 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand.
authors: Warisara
authors: W
authors: Parichatikanond
authors: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University , 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand.
authors: Kuntarat
authors: K
authors: Arunrungvichian
authors: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf , Permoserstraße15, 04318 Leipzig, Germany.
authors: Steffen
authors: S
authors: Fischer
authors: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University , Chiang Mai 50200, Thailand.
authors: Siriporn
authors: S
authors: Chattipakorn
authors: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf , Permoserstraße15, 04318 Leipzig, Germany.
authors: Winnie
authors: W
authors: Deuther-Conrad
authors: Department of Ecological Chemistry, Helmholtz Centre for Environmental Research-UFZ, Permoserstraße15, 04318 Leipzig, Germany; Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Straße29, 09596 Freiberg, Germany.
authors: Gerrit
authors: G
authors: Schüürmann
authors: Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf , Permoserstraße15, 04318 Leipzig, Germany.
authors: Peter
authors: P
authors: Brust
authors: Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University , 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand.
authors: Opa
authors: O
authors: Vajragupta
keywords: Nicotinic acetylcholine receptor; click chemistry; positron emission tomography; quinuclidine anti-1,2,3-triazole