Deligia_2015_Eur.J.Med.Chem_103_429

New analogues (3a-l) of the previously described alpha4beta2 selective ligand 3-(6-halopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptanes (2a,b) have been synthesized and their binding activity for neuronal acetylcholine receptor subtypes alpha4beta2 and alpha7 were assayed. Six of these compounds (3a,b,c,j,k and l) showed high affinity and selectivity for alpha4beta2 receptors. The phenylpyridyl-diazabicycloheptane 3c displayed Ki value of 11.17 pM for alpha4beta2, in line with that of the halogenated homologues 3a,b, although it was characterized by an improved selectivity (Ki = 17 muM for alpha7 receptors). The influence of substitutions on the phenylpyridyl moiety on binding at both alpha4beta2 and alpha7 receptors has been examined through the Topliss decision tree analysis. Substitution with electron-donating groups (as CH3 and OCH3) resulted in a good affinity for alpha4beta2 receptors and substantially no affinity for alpha7. Amongst all the tested phenyl-substituted compounds, the p-NO2-phenyl substituted analogue 3j exhibited the highest alpha4beta2 affinity, with Ki value comparable to that of 3c. Intrinsic alpha4beta2 receptor mediated activity in [(3)H]-DA release assay was showed by compound 3a as well as by the reference analogue 2a, whereas phenyl substituted derivative 3c exhibited alpha4beta2 antagonist activity.