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

The novel quinuclidine -1,2,3-triazole derivatives - were designed based on the structure of . 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 ()-enantiomers are selective to α7 over α4β2 (by factors of 44-225) and to a smaller degree over α3β4 (3-33), their ()-counterparts prefer α3β4 over α4β2 (62-237) as well as over α7 (5-294). The ()-derivatives were highly selective to α7 over α3β4 subtypes compared to ()- and ()-. The ()-enantiomers are 5-10 times more selective to α4β2 than their () forms. The overall strongest affinity is observed for the ()-enantiomer binding to α3β4 (, 2.25-19.5 nM) followed by their ()-counterpart binding to α7 (, 22.5-117 nM), with a significantly weaker ()-enantiomer binding to α4β2 (, 414-1980 nM) still above the very weak respective ()-analogue affinity (, 5059-10436 nM).