Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds

摘要: The novel quinuclidine anti-1,2,3-triazole derivatives T1–T6 were designed based on the structure of QND8. binding studies revealed that stereochemistry at C3 position scaffold plays an important role in nAChR subtype selectivity. Whereas (R)-enantiomers are selective to α7 over α4β2 (by factors 44–225) and a smaller degree α3β4 (3–33), their (S)-counterparts prefer (62–237) as well (5–294). (R)-derivatives highly subtypes compared (RS)- (R)-QND8. (S)-enantiomers 5–10 times more than (R) forms. overall strongest affinity is observed for (S)-enantiomer (Ki, 2.25–19.5 nM) followed by (R)-counterpart 22.5–117 nM), with significantly weaker 414–1980 still above very weak respective (R)-analogue 5059–10436 nM).