具有双重 SSRI 和 5-HT(1A) 活性的新型 4-芳基-吡啶并[1,2-c]嘧啶。第 3 部分。
Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. part 3.
机构信息
Department of Drug Technology, Faculty of Pharmacy, Medical University of Warsaw, ul. Banacha 1, 02-097 Warszawa, Poland.
出版信息
Eur J Med Chem. 2011 Jan;46(1):142-9. doi: 10.1016/j.ejmech.2010.10.026. Epub 2010 Oct 29.
A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT(1A)/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT(1A) and SERT with K(i) ranging from 28,3 to 642 nM and 42,4 nM-1,8 μM, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 8i as an antagonist of 5-HT(1A) presynaptic receptors in the inducible hypothermia test in mice.
为了进一步研究具有双重 5-HT(1A)/SERT 活性的吡啶并[1,2-c]嘧啶衍生物的 SAR，我们合成了一系列带有 3-(1,2,3,6-四氢-吡啶-4-基)-1H-吲哚或 2-甲基-3-(1,2,3,6-四氢-吡啶-4-基)-1H-吲哚残基的 4-芳基-5,6,7,8-四氢吡啶并[1,2-c]嘧啶。发现化合物 8a-8p 是 5-HT(1A)和 SERT 的有效配体，Ki 值分别为 28.3-642 nM 和 42.4 nM-1.8 μM。此外，化合物 8a、8b、8c、8d、8e 和 8g 被发现是 5-HT(1A)的选择性激动剂，而 8i 在诱导性体温降低试验中是 5-HT(1A)突触前受体的拮抗剂。
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