Jellimann C, Mathé-Allainmat M, Andrieux J, Kloubert S, Boutin J A, Nicolas J P, Bennejean C, Delagrange P, Langlois M
Faculté de Pharmacie, Université de Paris-Sud, CNRS-BIOCIS (UPRES A 8076), 5 rue J. B. Clément, 92296 Châtenay-Malabry, France.
J Med Chem. 2000 Nov 2;43(22):4051-62. doi: 10.1021/jm000922c.
Conformationally restricted phenalene and acenaphthene derivatives 5 were synthesized from phenalen-1-one and acenaphthen-1-one derivatives using the Horner-Emmons reaction. The amines were prepared through the corresponding isocyanates by the Curtius reaction on the acids or by the reduction of the nitriles. Amido derivatives (R(3) = Me, Et, n-Pr, c-Pr) were prepared by acylation of the amines with the appropriate anhydrides or acid chlorides or by the reductive acylation of the nitriles. The affinities of the compounds for melatonin binding sites were evaluated in vitro in binding assays using chicken brain melatonin and the human mt(1) and MT(2) receptors expressed in HEK-293 cells. The functionality of the compounds was determined by the potency to lighten the skin of Xenopus laevis tadpoles. Highly potent compounds were obtained. The data highlighted the role of the methoxy group located in the ortho position to the ethylamido chain as compounds with picomolar affinities such as 14c were obtained (chicken brain, hmt(1), hMT(2) K(i) values = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent to the corresponding dimethoxy derivative 15c (chicken brain, hmt(1), hMT(2) K(i) values = 0.07, 0.016, 0.1 nM, respectively). On the other hand, the restricted conformation of the amido chain did not influence selectivity for the cloned hmt(1) and hMT(2) receptors. These compounds were also potent agonists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC(50) = 0.025, 0.004 nM, respectively). Conformational studies indicated that the minimum energy folded conformation of the ethylamido chain could constitute the putative active form in the receptor site in agreement with previous results.
通过霍纳-埃蒙斯反应，由菲-1-酮和苊-1-酮衍生物合成了构象受限的菲和苊衍生物5。胺是通过相应的异氰酸酯，由酸上的库尔提斯反应或腈的还原制备的。酰胺衍生物（R(3)=甲基、乙基、正丙基、环丙基）是通过用适当的酸酐或酰氯对胺进行酰化，或通过腈的还原酰化制备的。使用鸡脑褪黑素以及在HEK-293细胞中表达的人mt(1)和MT(2)受体，通过结合试验在体外评估了这些化合物对褪黑素结合位点的亲和力。通过使非洲爪蟾蝌蚪皮肤变浅的效力来确定这些化合物的功能。获得了高效能的化合物。数据突出了位于乙酰胺链邻位的甲氧基的作用，因为获得了具有皮摩尔亲和力的化合物，如14c（鸡脑、hmt(1)、hMT(2)的K(i)值分别为0.02、0.008、0.069 nM）。化合物14c与相应的二甲氧基衍生物15c效力相当（鸡脑、hmt(1)、hMT(2)的K(i)值分别为0.07、0.016、0.1 nM）。另一方面，酰胺链的受限构象不影响对克隆的hmt(1)和hMT(2)受体的选择性。这些化合物也是非洲爪蟾中黑素细胞聚集的有效激动剂。15a、c的效力比褪黑素高几百倍（EC(50)分别为0.025、0.004 nM）。构象研究表明，乙酰胺链的最低能量折叠构象可能构成受体位点中的假定活性形式，这与先前的结果一致。
