In silico design of agonists targeting the alpha7 nicotinic acetylcholine receptors, their synthesis and preliminary pharmacological evaluation

As an extension of previous molecular modeling studies on nicotinic acetylcholine receptor (nAChR) ligands,[1] we now adopted the LIR (Linear Interaction Response) approach to reach a realistic compromise between accuracy and calculation rate, during the delta(G)bind value estimation of a training set of known agonists for the alpha7 nAChR subtype. The same strategy was applied to a text set of potential alpha7 nAChR agonists, which allowed identification of general structures A and B as the most promising ligands in the series. Thus, some of these derivatives were synthesized along with procedures previously utilized by us,[2] and were then assayed for binding affinity at alpha7 and alpha4beta2 nAChR subtypes. [1] Grazioso, G.; Cavalli, A.; De Amici, M.; Recanatini, M.; De Micheli, C. J. Comput. Chem. 2008, 29, 2593-2602. [2] Rizzi, L.; Dallanoce, C.; Matera, C.; Magrone, P.; Pucci, L.; Gotti, C.; Clementi, F.; De Amici, M. Bioorg. Med. Chem. Lett. 2008, 18, 4651-4654.