Design and synthesis of 3-phenyltetrahydronaphthalenic derivatives as new selective MT2 melatoninergic ligands. Part II

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 8; pp. 2963 - 2974
• Main Authors: DURIEUX, Sophie, CHANU, Angéline, LESIEUR, Daniel, BERTHELOT, Pascal, YOUS, Saïd, BOCHU, Christophe, AUDINOT, Valérie, COUMAILLEAU, Sophie, BOUTIN, Jean A, DELAGRANGE, Philippe, CAIGNARD, Daniel H, BENNEJEAN, Caroline, RENARD, Pierre
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.04.2009
• Subjects: Animals; Biological and medical sciences; Cell Culture Techniques; Cell Line; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Drug Design; Ligands; Medical sciences; Melatonin - analogs & derivatives; Melatonin - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Receptor, Melatonin, MT2 - chemistry; Receptor, Melatonin, MT2 - metabolism; Structure-Activity Relationship; Substrate Specificity; Tetrahydronaphthalenes - chemical synthesis; Tetrahydronaphthalenes - pharmacology; Transfection; Partial agonist; Five membered ring; Melatonin; Ether; Tetralins; Nitrogen heterocycle; Lactam; Selectivity; Naphthalene derivatives; In vitro; Selective antagonists; Structure activity relation; Bicyclic compound; Affinity; Carboxamide; Aromatic compound; Antagonist; MT2 melatonin receptor; Chemical synthesis; MT2 receptors; Halogen Organic compounds
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.03.023

Following our studies of the melatoninergic receptors, we have developed new tetrahydronaphthalenic derivatives of melatonin that have been tested as selective melatonin receptors ligands. Regarding the role of the phenyl substituent to obtain selective ligands, modulation of selectivity and activity have been achieved by modifications of the acyl group and substitutions on the phenyl ring. Ten of the seventeen evaluated derivatives have MT(2) receptor affinity similar to that of melatonin. Moreover, we have achieved remarkable MT(2) selectivity over MT(1) (selectivity >100) and have been able to further extend the RSA of the tetrahydrophthalenic series. However, the compounds presented here display partial agonist or antagonist behavior instead of full agonist.