New melatonin (MT1/MT2) ligands: Design and synthesis of (8,9-dihydro-7H-furo[3,2-f]chromen-1-yl) derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 3; pp. 986 - 996
• Main Authors: Landagaray, Elodie, Ettaoussi, Mohamed, Leclerc, Véronique, Traoré, Balla, Perez, Valérie, Nosjean, Olivier, Boutin, Jean A., Caignard, Daniel-Henri, Delagrange, Philippe, Berthelot, Pascal, Yous, Saïd
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2014; Elsevier
• Subjects: [35S]-GTPγS; Amides - chemistry; Animals; Benzofuran derivatives; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - metabolism; Biochemistry & Molecular Biology; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Chemistry, Organic; Chinese Hamster Ovary; CHO; CHO Cells - drug effects; Cricetulus; guanosine-5′[γ-35S]-triphosphate; HEK; HEK293 Cells - drug effects; Human Embryonic Kidney; Humans; Life Sciences & Biomedicine; Ligands; melatonin; Melatonin - agonists; Melatonin - analogs & derivatives; Melatonin - metabolism; MLT; MT1; MT2-selectivity; Pharmacology & Pharmacy; Physical Sciences; Receptor, Melatonin, MT1 - metabolism; Receptor, Melatonin, MT2 - metabolism; Science & Technology; Structure-Activity Relationship; Melatonin; MLT; MT2-selectivity; [35S]-GTPγS; CHO; Benzofuran derivatives; MT1; HEK; SERIES; ANALOGS; RECEPTOR AGONISTS; CONFORMATIONALLY-RESTRICTED LIGANDS; PINEAL-GLAND; DISORDERS; MECHANISMS; CANCER; SELECTIVE LIGANDS; EXOGENOUS MELATONIN; Chinese Hamster Ovary; Human Embryonic Kidney; MT; [S]-GTPγS; MT-selectivity; guanosine-5′[γ-S]-triphosphate
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.12.054

Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT1 and MT2 ligands. Most of the synthesized compounds displayed high binding affinities at MT1 and MT2 receptors subtypes. Compound 6b (MT1, Ki=0.07nM; MT2, Ki=0.08nM) exhibited with the vinyl 6c and allyl 6d the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC50 in the nanomolar range. Compounds 6a (EC50=0.8nM and Emax=98%) and 6b (EC50=0.2nM and Emax=121%) exhibited good pharmacological profiles.