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

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 ( K i , 2.25-19.5 nM) followed by their ( R )-counterpart binding to α7 ( K i , 22.5-117 nM), with a significantly weaker ( S )-enantiomer binding to α4β2 ( K i , 414-1980 nM) still above the very weak respective ( R )-analogue affinity ( K i , 5059-10436 nM).