Expeditious Synthesis, Enantiomeric Resolution, and Enantiomer Functional Characterization of (4-(4-Bromophenyl)-3a,4,5,9b-tetrahydro‑3H‑cyclopenta[c]quinoline-8-sulfonamide (4BP-TQS): An Allosteric Agonist-Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors

• Published in: Journal of medicinal chemistry Vol. 56; no. 21; pp. 8943 - 8947
• Main Authors: Thakur, Ganesh A, Kulkarni, Abhijit R, Deschamps, Jeffrey R, Papke, Roger L
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.11.2013
• Subjects: Allosteric Regulation - drug effects; alpha7 Nicotinic Acetylcholine Receptor - agonists; Animals; Binding Sites - drug effects; Crystallography, X-Ray; Dose-Response Relationship, Drug; Microwaves; Models, Molecular; Molecular Structure; Oocytes - chemistry; Oocytes - drug effects; Oocytes - metabolism; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Xenopus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401267t

An expeditious microwave-assisted synthesis of 4BP-TQS, its enantiomeric separation, and their functional evaluation is reported. Electrophysiological characterization in Xenopus oocytes revealed that activity exclusively resided in the (+)-enantiomer 1b (GAT107) and (−)-enantiomer 1a did not affect its activity when coapplied. X-ray crystallography studies revealed the absolute stereochemistry of 1b to be 3aR,4S,9bS. 1b represents the most potent ago-PAM of α7 nAChRs available to date and is considered for further in vivo evaluation.