Novel class of arylpiperazines containing N-acylated amino acids: Their synthesis, 5-HT1A, 5-HT2A receptor affinity, and in vivo pharmacological evaluation
| Autor: | Ewa Tatarczyńska, Maciej Pawłowski, Andrzej J. Bojarski, Agnieszka Nikiforuk, Gilles Subra, Ewa Chojnacka-Wójcik, Paweł Zajdel, Beata Duszyńska, Jean Martinez |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
Agonist Spectrometry Mass Electrospray Ionization medicine.drug_class Stereochemistry Clinical Biochemistry Pharmaceutical Science Anxiety In Vitro Techniques Motor Activity Biochemistry Partial agonist Piperazines Body Temperature Mice Serotonin Agents Solid-phase synthesis In vivo Drug Discovery medicine Animals Receptor Serotonin 5-HT2A Amino Acids Rats Wistar Receptor Molecular Biology Swimming chemistry.chemical_classification 8-Hydroxy-2-(di-n-propylamino)tetralin Receptors Dopamine D2 Chemistry Organic Chemistry Biological activity Ligand (biochemistry) Antidepressive Agents Rats Serotonin Receptor Agonists Amino acid Mice Inbred C57BL Anti-Anxiety Agents Hindlimb Suspension Receptor Serotonin 5-HT1A Molecular Medicine Indicators and Reagents Chromatography Thin Layer |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:2907-2919 |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect