Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, Poland.
Int J Mol Sci. 2021 Feb 26;22(5):2329. doi: 10.3390/ijms22052329.
Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a-i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine () derivatives were synthesized. The chemical structures of the new compounds were confirmed by H and C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT receptor of all derivatives in the series ( and ) and generally low binding affinities for the SERT protein, with the exception of compounds and . Extended affinity tests for the receptors D, 5-HT, 5-HT and 5-HT were conducted with regard to selected compounds (, , and ). All four compounds demonstrated very high affinities for the D and 5-HT receptors. Compounds and also had high affinities for 5-HT, while and held moderate affinities for this receptor. Compounds and were also tested in vivo to identify their functional activity profiles with regard to the 5-HT receptor, with demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for and .
合成了两个系列的新型 4-芳基-2H-吡啶并[1,2-c]嘧啶（6a-i）和 4-芳基-5,6,7,8-四氢吡啶并[1,2-c]嘧啶衍生物。新化合物的化学结构通过 1 H 和 13 C NMR 光谱和 ESI-HRMS 光谱确认。通过体外放射性配体结合试验测定了所有化合物对 5-HT 受体和血清素转运蛋白（SERT）的亲和力。测试化合物对该系列中所有衍生物（和）的 5-HT 受体表现出非常高的结合亲和力，通常对 SERT 蛋白的结合亲和力较低，但化合物和除外。对选定化合物（，，和）进行了受体 D、5-HT、5-HT 和 5-HT 的扩展亲和力测试。这四个化合物对 D 和 5-HT 受体均表现出非常高的亲和力。化合物和对 5-HT 受体也具有高亲和力，而化合物和对该受体具有中等亲和力。化合物和还在体内进行了测试，以确定它们对 5-HT 受体的功能活性谱，化合物表现出前突触激动剂的活性谱。还对和进行了代谢稳定性测试。
