Kucwaj-Brysz Katarzyna, Kurczab Rafał, Żesławska Ewa, Lubelska Annamaria, Marć Małgorzata Anna, Latacz Gniewomir, Satała Grzegorz, Nitek Wojciech, Kieć-Kononowicz Katarzyna, Handzlik Jadwiga
Department of Technology and Biotechnology of Drugs , Jagiellonian University Medical College , Medyczna 9 , 30-688 Cracow , Poland . Email:
Department of Medicinal Chemistry Institute of Pharmacology , Polish Academy of Science , Smętna 12 , 31-343 , Cracow , Poland.
Medchemcomm. 2018 May 8;9(6):1033-1044. doi: 10.1039/c8md00168e. eCollection 2018 Jun 1.
In order to search for active and selective serotonin 5-HTR antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione (, KKB16) were performed. New derivatives () were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione () was performed to support molecular modeling and SAR studies. The affinity for 5-HTR, DR and 5-HTR in radioligand binding assays for the entire series and ADME-Tox parameters for selected compounds (, , and ) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HTR agents ( ≤ 5 nM) with significant selectivity over 5-HTR and DR. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HTR/5-HTR action (: 11 nM/19 nM).
为了在3,5-二取代芳基哌嗪-咪唑烷-2,4-二酮中寻找活性和选择性5-羟色胺受体（5-HTR）拮抗剂，分析了芳环引入/缺失的作用以及芳环的相互取向。对3-(3-(4-(二苯甲基)哌嗪-1-基)-2-羟丙基)-5-(4-氟苯基)-5-甲基咪唑烷-2,4-二酮（KKB16）的第二代先导结构进行了化学修饰。设计并合成了新的衍生物。对代表性化合物5-(4-氟苯基)-3-[2-羟基-3-(4-苯基哌嗪-1-基)丙基]-5-甲基咪唑烷-2,4-二酮进行了X射线晶体学分析，以支持分子建模和构效关系（SAR）研究。评估了整个系列在放射性配体结合试验中对5-HTR、多巴胺受体（DR）和5-HTR的亲和力以及所选化合物（、和）的药物代谢动力学和毒理学（ADME-Tox）参数。进行了分子对接和药效团模型评估。根据所得结果，发现5-甲基-5-萘基乙内酰脲衍生物是新型高活性5-HTR剂（≤5 nM），对5-HTR和DR具有显著选择性。相反，(1-萘基)哌嗪部分具有强效的5-HTR/5-HTR双重作用（：11 nM/19 nM）。
