Stefanowicz Jacek, Słowiński Tomasz, Wróbel Martyna Z, Ślifirski Grzegorz, Dawidowski Maciej, Stefanowicz Zdzisława, Jastrzębska-Więsek Magdalena, Partyka Anna, Wesołowska Anna, Turło Jadwiga
1Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.
2Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.
Med Chem Res. 2018;27(8):1906-1928. doi: 10.1007/s00044-018-2203-z. Epub 2018 Jun 22.
This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3β-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3βaminotropane derivatives was evaluated for their affinity for 5-HT, 5-HT, and D receptors, which allowed for the identification of compounds , , and as ligands with highest affinity for the tested receptors; they were then subjected to further evaluation in preliminary in vivo studies. Selected compounds and displayed antipsychotic properties in the d-amphetamine-induced and MK-801-induced hyperlocomotor activity test in mice. Moreover, compound showed significant antidepressant-like activity in the forced swim test in mice.
本研究是我们之前研究的延续，此次重点在于对先导结构进行修饰，以提高所设计化合物对5-羟色胺（5-HT）受体的亲和力及水溶性。因此，本项目合成的化合物包括托烷3β-酰胺衍生物的结构类似物，其中苄环引入了甲基取代基，并带有2-喹啉、3-喹啉或6-喹啉部分。对一系列新型3β-氨基托烷衍生物进行了5-HT、5-HT及多巴胺（D）受体亲和力评估，从而鉴定出化合物 、 和 为对受试受体具有最高亲和力的配体；随后对它们进行了初步体内研究的进一步评估。所选化合物 和 在小鼠d-苯丙胺诱导及MK-801诱导的运动亢进活性试验中表现出抗精神病特性。此外，化合物 在小鼠强迫游泳试验中显示出显著的类抗抑郁活性。
