Design of novel 3,6-diazabicyclo[3.1.1]heptane derivatives with potent and selective affinities for alpha(4)beta(2) neuronal nicotinic acetylcholine receptors

New analogues (3a-l) of the previously described ?4?2 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 ?4?2 and ?7 were assayed.Six of these compounds (3a,b,c,j,k and l) showed high affinity and selectivity for ?4?2 receptors. The phenylpyridyl-diazabicycloheptane 3c displayed Ki value of 11.17 pM for ?4?2, in line with that of the halogenated homologues 3a,b, although it was characterized by an improved selectivity (Ki = 17 ?M for ?7 receptors). The influence of substitutions on the phenylpyridyl moiety on binding at both ?4?2 and ?7 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 ?4?2 receptors and substantially no affinity for ?7. Amongst all the tested phenyl-substituted compounds, the p-NO2-phenyl substituted analogue 3j exhibited the highest ?4?2 affinity, with Ki value comparable to that of 3c.Intrinsic ?4?2 receptor mediated activity in [3H]-DA release assay was showed by compound 3a as well as by the reference analogue 2a, whereas phenyl substituted derivative 3c exhibited ?4?2 antagonist activity