Conformational analysis and theoretical quantitative size and shape-affinity relationships of N-4-protonated N-1-arylpiperazine 5-HT1A serotoninergic ligands

Conformational analysis for 24 arylpiperazines in their neutral and N-4-protonated forms has been performed in the AM1 framework. Both these derivatives and eight reference compounds considered in this study are ligands of the 5-HT1A serotoninergic receptor. Quantum chemical reactivity indices, solvation free energies (AMSOL 5.0) and molecular modelling derived ad hoc size and shape descriptors have been computed and correlated with the literature 5-HT1A binding affinity data values. The quantitative size-shape affinity relationships obtained confirm the validity and versatility of the ad hoc descriptors employed. A different role has been postulated for the neutral and protonated forms of the arylpiperazines considered in the molecular recognition process of the 5-HT1A receptor binding site.