Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors

Conformationally restricted phenalene and acenaphthene derivatives 5 were s ynthesized 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 ac ylation 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 usin g chicken brain melatonin and the human mt(1) and MT2 receptors expressed i n HEK-293 cells. The functionality of the compounds was determined by the p otency to lighten the skin of Xenopus laevis tadpoles. Highly potent compou nds were obtained. The data highlighted the role of the methoxy group locat ed in the ortho position to the ethylamido chain as compounds with picomola r affinities such as 14c were obtained (chicken brain, hmt(1), hMT(2) K-i v alues = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent t o 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 re stricted conformation of the amido chain did not influence selectivity for the cloned hmt(1) and hMT(2) receptors. These compounds were also potent ag onists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC50 = 0.025, 0.004 nM, respectively). Con formational studies indicated that the minimum energy folded conformation o f the ethylamido chain could constitute the putative active form in the rec eptor site in agreement; with previous results.