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Synthesis of Phenalene and Acenaphthene Derivatives as New Conformationally Restricted Ligands for Melatonin Receptors

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Faculté de Pharmacie, Université de Paris-Sud, CNRS−BIOCIS (UPRES A 8076), 5 rue J. B. Clément, 92296 Châtenay-Malabry, France, Institut de Recherche Servier, Centre de Croissy, 125 Chemin de Ronde, 78290 Croissy sur Seine, France, Institut de Recherche Internationale Servier, Place des Pléiades, 92415 Courbevoie, France, and ADIR, 1 rue Carle Hébert, 92415 Courbevoie, France
Cite this: J. Med. Chem. 2000, 43, 22, 4051–4062
Publication Date (Web):October 14, 2000
Copyright © 2000 American Chemical Society

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    Abstract Image

    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 (R3 = 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 mt1 and MT2 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, hmt1, hMT2Ki values = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent to the corresponding dimethoxy derivative 15c (chicken brain, hmt1, hMT2Ki 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 hmt1 and hMT2 receptors. These compounds were also potent agonists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC50 = 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.

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     Institut de Recherche Servier.


     Institut de Recherche Internationale Servier.


     To whom correspondence should be addressed. Tel:  33 1 46 83 57 36. Fax:  33 1 46 83 57 40. E-mail:  [email protected].

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