Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
Eur J Med Chem. 2014 May 6;78:10-22. doi: 10.1016/j.ejmech.2014.03.005. Epub 2014 Mar 5.
A 47-membered library of novel long-chain arylpiperazines, which contained cyclic amino acid amides in the terminal fragment (pyrrolidine-2-carboxamide and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide), was synthesized on Rink-amide resin and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Surprisingly, members of the designed series containing piperidine-2-carboxamide fragments underwent hydrolysis, which occurred during the acidic treatment for release from the solid-support, to their respective pipecolic acid analogs. Representative compounds from the library displayed high-to-low affinity for 5-HT7 (Ki = 18-3134 nM) and 5-HT1A (Ki = 0.5-6307 nM) sites. The possible interactions implicated in binding of the studied compounds to the 5-HT7 receptor were supported by molecular modeling. Research was also applied to support the exploration of the influence of the amide fragment, the length of alkylene spacer, and arylpiperazine substituents on the receptor's affinity and selectivity.
合成了一个由 47 个新型长链芳基哌嗪组成的文库，其中末端片段（吡咯烷-2-甲酰胺和 1,2,3,4-四氢异喹啉-3-甲酰胺）含有环状氨基酸酰胺。这些化合物被生物评估了对 5-HT7 和 5-HT1A 受体的结合亲和力。令人惊讶的是，设计的含有哌啶-2-甲酰胺片段的系列成员经历了水解，这是在酸性处理中从固体载体上释放时发生的，生成了各自的哌啶酸类似物。文库中的代表性化合物对 5-HT7（Ki=18-3134nM）和 5-HT1A（Ki=0.5-6307nM）位点表现出高到低的亲和力。研究还应用于支持对研究化合物与 5-HT7 受体结合的可能相互作用的分子建模。研究还探索了酰胺片段、亚烷基间隔物的长度和芳基哌嗪取代基对受体亲和力和选择性的影响。
