Novel class of arylpiperazines containing N-acylated amino acids: Their synthesis, 5-HT_1A, 5-HT_2A receptor affinity, and in vivo pharmacological evaluation

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• 作者：Paweł ; Zajdel ; Gilles Subra ; Andrzej J. Bojarski ; Beata Duszyń ; ska ; Ewa Tatarczyń ; ska ; Agnieszka Nikiforuk ; Ewa Chojnacka-W&#xf3 ; jcik ; Maciej Pawł ; owski ; Jean Martinez
• 关键词：Long-chain arylpiperazines ; Succinimides ; Pyrrolidine-2 ; 5-dione ; Prolinamides ; Solid-phase synthesis ; 5-HT_1A/5-HT_2A receptor ligands ; 5-HT_1A receptor agonists ; Four-plate test ; Forced swimming test ; Tail suspension test
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2007
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 April 2007
• 卷：15
• 期：8
• 页码：2907-2919
• 文件大小：272 K

摘要

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 D₂ receptors was evaluated. The compounds bearing (3-acylamino)pyrrolidine-2,5-dione (trong>19trong>–trong>26trong>) and N-acylprolinamide (trong>29trong>–trong>34trong>) 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 D₂ 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 (trong>29trong>) 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 trong>19trong> and trong>20trong>, a 5-HT_1A partial agonist and a full agonist, respectively, and trong>26trong>, 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 trong>20trong> 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.