title: Novel class of arylpiperazines containing N-acylated amino acids: their synthesis, 5-HT1A, 5-HT2A receptor affinity, and in vivo pharmacological evaluation.
abstract: 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.
authors.affiliation: Laboratoire des Aminoacides, Peptides et Protéines (LAPP), UMR 5810, Faculté de Pharmacie, Université Montpellier I et II, 15 Avenue Charles Flahault, 34060 Montpellier, France. mfzajdel@cyf-kr.edu.pl
authors.forename: Paweł
authors.initials: P
authors.lastname: Zajdel
authors.forename: Gilles
authors.initials: G
authors.lastname: Subra
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Beata
authors.initials: B
authors.lastname: Duszyńska
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Nikiforuk
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001831:Body Temperature / Q000187:drug effects; D002855:Chromatography, Thin Layer; D019417:Hindlimb Suspension; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013550:Swimming / Q000523:psychology
chemical_list: D000596:Amino Acids; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D007202:Indicators and Reagents; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin