Résumé
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-HT
1A, 5-HT
2A, and D
2 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-HT
1A (
K
i
=
3–47
nM), high-to-low for 5-HT
2A (
K
i
=
4.2–990
nM), and low for D
2 receptors (
K
i
=
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-HT
1A 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-HT
1A partial agonist and a full agonist, respectively, and
26, a mixed 5-HT
1A/5-HT
2A 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.