1-Aryl-4-(4-succinimidobutyl)piperazines and their conformationally constrained analogues: synthesis, binding to serotonin (5-HT1A, 5-HT2A, 5-HT7), α1-adrenergic, and dopaminergic D2 receptors, and in vivo 5-HT1A functional characteristics Original Resear

Starting with the structure of potent 5-HT1A ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R = H, m-Cl, m-CF3, m-OCH3, p-OCH3) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT1A affinity, selectivity for 5-HT2A, 5-HT7, D1, and D2 binding sites and functional profile at pre- and postsynaptic 5-HT1A receptors. The new compounds 19–25 were found to be highly active 5-HT1A receptor ligands (Ki = 4–44 nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT7), or controlled by substituents in the aromatic ring (α1), or influenced by both those structural modifications (5-HT2A), or very low (D2, Ki = 5.3–31 μM). Since a distinct disfavor towards rigid compounds was observed for 5-HT7 receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one.