Jellimann C, Mathé-Allainmat M, Andrieux J, Renard P, Delagrange P, Langlois M
CNRS-BIOCIS (URA 1843), Faculté de Pharmacie, Université de Paris-Sud, 5 rue J. B. Clément, 92296 Châtenay-Malabry, France.
J Med Chem. 1999 Mar 25;42(6):1100-5. doi: 10.1021/jm9804937.
N-(4-Methoxy-2,3-dihydro-1H-phenalen-2-yl)amide derivatives, conformationally restricted ligands for melatonin receptors, were synthesized by an alternative synthetic method from the corresponding 1,8-naphthalic anhydride which was transformed into the phenalenecarboxylic acid 7. A Curtius reaction on 7 gave the amino compound which was acylated to give compounds 4a-c. The (+)- and (-)-4a-c enantiomers were separated by semipreparative chiral HPLC. Compounds were evaluated for their affinity for chicken brain melatonin receptors in binding assays using 2-[125I]iodomelatonin and for their potency to lighten the skin of Xenopus laevis tadpoles. The butyramido derivative 4c was the most potent ligand (Ki = 1.7 nM). No enantioselectivity was observed with the enantiomers which were equipotent to the racemic mixture. In contrast to the reference compounds, melatonin, agomelatine (S 20098), and N-[2-(2, 7-dimethoxynaphth-1-yl)ethyl]acetamide, which were very potent at lightening the skin of X. laevis tadpoles, compounds 4a-c were inactive or weakly active (EC50 > 1 microM). In this bioassay, compound 4a was characterized as a putative antagonist of melatonin receptors.
N-（4-甲氧基-2,3-二氢-1H-菲-2-基）酰胺衍生物是褪黑素受体的构象受限配体，通过另一种合成方法由相应的1,8-萘二甲酸酐合成，该酸酐转化为菲羧酸7。对7进行库尔提斯反应得到氨基化合物，该氨基化合物经酰化得到化合物4a - c。通过半制备型手性高效液相色谱法分离出（+）-和（-）-4a - c对映体。在使用2-[125I]碘褪黑素的结合试验中评估了化合物对鸡脑褪黑素受体的亲和力，以及它们使非洲爪蟾蝌蚪皮肤变浅的效力。丁酰胺基衍生物4c是最有效的配体（Ki = 1.7 nM）。对映体之间未观察到对映选择性，它们与外消旋混合物的效力相当。与参考化合物褪黑素、阿戈美拉汀（S 20098）和N-[2-（2,7-二甲氧基萘-1-基）乙基]乙酰胺不同，这些参考化合物在使非洲爪蟾蝌蚪皮肤变浅方面非常有效，而化合物4a - c无活性或活性较弱（EC50 > 1 microM）。在该生物测定中，化合物4a被表征为褪黑素受体的假定拮抗剂。
