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

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• 作者：Elodie L ; agaray ; Mohamed Ettaoussi ; V茅ronique Leclerc ; Balla Traor茅 ; Val茅rie Perez ; Olivier Nosjean ; Jean A. Boutin ; Daniel-Henri Caignard ; Philippe Delagrange ; Pascal Berthelot ; Sa茂d Yous
• 关键词：[35S]-GTP纬S ; guanosine-5&prime ; [纬-35S]-triphosphate ; CHO ; Chinese Hamster Ovary ; HEK ; Human Embryonic Kidney ; MLT ; melatonin
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 February, 2014
• 年：2014
• 卷：22
• 期：3
• 页码：986-996
• 全文大小：616 K

文摘

Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT<sub>1sub> and MT<sub>2sub> ligands. Most of the synthesized compounds displayed high binding affinities at MT<sub>1sub> and MT<sub>2sub> receptors subtypes. Compound <strong class="boldFont">6bstrong> (MT<sub>1sub>, K<sub>isub> = 0.07 nM; MT<sub>2sub>, K<sub>isub> = 0.08 nM) exhibited with the vinyl <strong class="boldFont">6cstrong> and allyl <strong class="boldFont">6dstrong> the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC<sub>50sub> in the nanomolar range. Compounds <strong class="boldFont">6astrong> (EC<sub>50sub> = 0.8 nM and E<sub>maxsub> = 98%) and <strong class="boldFont">6bstrong> (EC<sub>50sub> = 0.2 nM and E<sub>maxsub> = 121%) exhibited good pharmacological profiles.