Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal nicotinic acetylcholine receptors

Α series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a–f was synthesized and their affinity and selectivity towards α4β2 and α7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for α4β2 (Ki at α4β2 ranging from 0.023 to 0.056 nM) versus α7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most α7α4β2 selective term in receptor binding assays (α7α4β2 = 1295). Moreover, compound 4d also had high affinity for the α4β2 nAChR subtype (Ki = 1.2 nM) with considerably high selectivity (α7/α4β2 = 23300).

A series of novel pyridyl 3,6-diazabicyclo[3.1.1]heptane (4a–f) α4β2 ligands was identified. SAR around pyridine moiety resulted in the discovery of compounds with affinities in the low nanomolar range.Figure optionsDownload as PowerPoint slide