6-Chloropyridazin-3-yl derivatives active as nicotinic agents: synthesis, binding, and modeling studies

3,8-Diazabicyclo[3.2.1]octane (1), 2,5-diazabicyclo[2.2.1]heptane (2), piperazine (3), and homopiperazine (4) derivatives, substituted at one nitrogen atom with the 6-chloro-3-pyridazinyl group while the other nitrogen atom was either unsubstituted or mono- or dimethylated, were synthesized and tested for their affinity toward the neuronal nicotinic acetylcholine receptors (nAChRs). All of the compounds had K(i) values in the nanomolar range. A molecular modeling study allowed location of their preferred conformations, the energies of which were recalculated in water with a continuum solvent model. Some of the compounds showed, in their populated conformations, only pharmacophoric distances longer than the values taken into consideration by the Sheridan model for nAChRs receptors. Thus, this SAR study gives support to the hypothesis that these longer distances are still compatible with affinity for alpha4beta2 receptors in the nanomolar range.