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

• Published in: Bioorganic & medicinal chemistry 2007-04, Vol.15 (8), p.2907-2919
• Main Authors: ZAJDEL, Paweł, SUBRA, Gilles, BOJARSKI, Andrzej J, DUSZNSKA, Beata, TATARCZYNSKA, Ewa, NIKIFORUK, Agnieszka, CHOJNACKA-WOJCIK, Ewa, PAWLOWSKI, Maciej, MARTINEZ, Jean
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Amino Acids - chemical synthesis; Amino Acids - pharmacology; Animals; Anti-Anxiety Agents - chemical synthesis; Anti-Anxiety Agents - pharmacology; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Anxiety - drug therapy; Anxiety - psychology; Biological and medical sciences; Body Temperature - drug effects; Catecholaminergic system; Chromatography, Thin Layer; Hindlimb Suspension; In Vitro Techniques; Indicators and Reagents; Male; Medical sciences; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - pharmacology; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - drug effects; Receptor, Serotonin, 5-HT1A - metabolism; Receptor, Serotonin, 5-HT2A - drug effects; Receptor, Serotonin, 5-HT2A - metabolism; Receptors, Dopamine D2 - drug effects; Serotonin Agents - chemical synthesis; Serotonin Agents - pharmacology; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Spectrometry, Mass, Electrospray Ionization; Swimming - psychology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.02.018

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 microM). 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.