Novel class of arylpiperazines containing N-acylated amino acids: Their synthesis, 5-HT1A, 5-HT2A receptor affinity, and in vivo pharmacological evaluation

Novel arylpiperazines with N-acylated amino acids, selected on the basis of a preliminary screening of two libraries previously synthesized on SynPhase™ Lanterns, were prepared in solution and their affinity for 5-HT1A, 5-HT2A, and D2 receptors was evaluated. The compounds bearing (3-acylamino)pyrrolidine-2,5-dione (19–26) and N-acylprolinamide (29–34) moieties showed high affinity for 5-HT1A (Ki = 3–47 nM), high-to-low for 5-HT2A (Ki = 4.2–990 nM), and low for D2 receptors (Ki = 0.77–21.19 μM). All the new o-methoxy derivatives of (3-acylamino)pyrrolidine-2,5-diones tested in vivo revealed agonistic activity at postsynaptic 5-HT1A receptors, while m-chloro derivatives were classified as antagonists of these sites; similar relations were observed for o-methoxy (29) and m-chlorophenylpiperazine derivatives of N-acylprolinamides. The reported results show that the amino acid-derived terminal fragment modified the in vivo functional profile. Finally, the selected compounds 19 and 20, a 5-HT1A partial agonist and a full agonist, respectively, and 26, a mixed 5-HT1A/5-HT2A antagonist, were evaluated in preclinical animal models of depression and anxiety. The project allowed selecting the lead compound 20 which exhibited an anxiolytic-like effect in the four-plate test in mice and revealed distinct antidepressant-like effects in the forced swimming and tail suspension tests in mice.

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