BACKGROUND & AIMS:
:Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.
背景与目标:
赛庚啶是对2型(5-HT2)受体具有高度亲和力的药物。我们研究了通过修饰Cyp(二苯并环庚二烯)的三环系统获得的一系列化合物:2f(噻吨并蒽),2g(并吨蒽),2h(二氢二苯并环庚二烯),2j(二苯基),2i(芴)和3b(苯甲基)。它们对大鼠大脑皮层5-HT2A受体的活性为(pKi /-SEM):8.80 /-0.11(Cyp),8.60 /-0.07(2f),8.40 /-0.02(2g),8.05 /-0.03(2h) ,7.87 /-0.12(2j),6.70 /-0.02(2i)和6.45 /-0.02(3b);大鼠胃底5-HT2B受体(pA2 / SEM)分别为9.14 /-0.25(Cyp),8.49 /-0.07(2f),7.58 /-0.58(2g),7.02 /-0.14(2h), 6.07 /-0.20(2j)和不可检测的(2i,3b):猪脉络丛5-HT2C受体(pKi /-SEM)分别为:8.71 /-0.08(Cyp),8.68 /-0.01(2f) ,8.58 /-0.20(2g),7.95 /-0.05(2h),7.57 /-0.04(2j),6.98 /-0.04(2i)和6.63 /-0.20(3b)。斜率与统一没有显着差异。这些化合物在每种受体上都表现出相同的活性顺序,活性最高的分子呈现出一定的空间(三环系统的蝴蝶构象)和静电(中心环顶部的质子亲和力)模式。结论是,赛庚啶衍生物对5-HT 2受体的活性与这些分子特征有关,这使得与所有三种5-HT 2亚型相互作用的共同配置成为可行。