Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A |
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| Institution: | 1. Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States;2. Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States;1. Institute of Chemistry and Chemical Technology, Siberian Branch of the Russian Academy of Sciences, Akademgorodok, 50-24, Krasnoyarsk 660036, Russia;2. Institute of Physics, Siberian Branch of the Russian Academy of Sciences, Akademgorodok, 50-38, Krasnoyarsk 660036, Russia;3. Krasnoyarsk Scientific Center of the Siberian Branch of the RAS, Akademgorodok, 50, Krasnoyarsk 660036, Russia;4. Siberian Federal University, Svobodny Prospect, 79, Krasnoyarsk 660041, Russia;1. Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan 475004, PR China;2. Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, PR China;1. Chemistry Department, Faculty of Science, Mu''tah University, Karak 61710, Jordan;2. Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan;3. College of Pharmacy, Taibah University, Al Madinah 41477, Saudi Arabia;4. Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy |
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| Abstract: | The enantiomers of two analogs of Sazetidine-A as well as several other novel biosteric analogues were synthesized. Their binding affinities at three major nAChRs subtypes and selectivity profiles were determined. Though many (S)-enantiomers of Sazetidine-A analogs have high binding affinities and good subtype selectivities, it is not a general rule that (S)-enantiomers are better than their (R) counterparts. Compound 11, of which the ethynyl group was replaced by its’ bioisostere—the triazole via click chemistry, showed a high binding affinity to α4β2 subtype (Ki = 1.3 nM) and better selectivity to the α4β2 subtype over α3β4 subtype with that of Sazetidine-A. The azide compound 15, a potential photoaffinity label, showed improved high selectivity and similar binding property profile with that of Sazetidine-A. The biaryl analog 17 exhibited a much lower affinity as compared to Sazetidine-A indicating the importance of a ‘long tail’ side chain for α4β2 nAChR binding. |
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| Keywords: | Sazetidine A nAChR α4β2 Nicotinic receptor Click chemistry Bioisostere Biostere Photoaffinity label |
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