Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT 1 /MT 2 ) and serotoninergic (5-HT 2C ) dual ligands

Romain Duroux (1) , Marouan Rami (2) , Elodie Landagaray (3) , Mohamed Ettaoussi (1) , Daniel-Henri Caignard , Philippe Delagrange (4) , Patricia Melnyk (5) , Saïd Yous (3)

1 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
2 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
3 ICPAL - Institut de Chimie Pharmaceutique Albert Lespagnol
4 Unité de Recherches et Découvertes en Neurosciences
5 IBLI - Institut de biologie de Lille - IBL

We recently reported a series of naphthofuranic compounds as constrained agomelatine analogues. Herein, in order to explore alternative ethyl amide side chain rigidification, naphthocyclopentane and quinolinocyclopentane derivatives with various acetamide modulations were synthesized and evaluated at both melatonin (MT1, MT2) and serotonin (5-HT2C) receptors. These modifications has led to compounds with promising dual affinity and high MTs receptors agonist activity. Enantiomeric separation was then performed on selected compounds allowing us to identify levogyre enantiomers (−)-17g and (−)-17k as the highest (MT1, MT2)/5-HT2C dual ligands described nowadays.

Mots clés: Melatonin; Serotonin; Agomelatine; Levogyre; Dextrogyre

Domaines: Chimie thérapeutique

Romain Duroux, Marouan Rami, Elodie Landagaray, Mohamed Ettaoussi, Daniel-Henri Caignard, et al.. Synthesis and biological evaluation of new naphtho- and quinolinocyclopentane derivatives as potent melatoninergic (MT 1 /MT 2 ) and serotoninergic (5-HT 2C ) dual ligands. European Journal of Medicinal Chemistry, 2017, 141, pp.552-566. ⟨10.1016/j.ejmech.2017.10.025⟩. ⟨hal-02011786⟩