Synthesis and Pharmacological Evaluation of a series of the Agomelatine Analogues as Melatonin MT₁/MT₂ Agonist and 5‐HT_2C Antagonist

Abstract

Agomelatine is a naphthalenic analogue of melatonin that is in clinical use for the treatment of major depressive disorders. Interestingly, while agomelatine exhibits potent affinity for melatonin receptors, it binds with only moderate affinity to the serotonin 5-HT2C receptor. Optimization of agomelatine toward this target could further potentiate its clinical efficacy. To explore this hypothesis and to access derivatives in which a key point of agomelatine metabolism is blocked, a series of naphthalenic derivatives was designed and synthesized as novel analogues of agomelatine. Most of the prepared compounds exhibited good binding affinity at the melatonin MT1 and MT2 receptor subtypes. Two compounds, an acetamide and an acrylamide derivative, exhibited good binding affinities at both the human melatonin (MT) receptors and the serotonin 5-HT2C receptor subtype, with pKi values of 7.96 and 7.95 against MT1, 7.86 and 8.68 against MT2, and 6.64 and 6.44 against 5-HT2C, respectively.

Melatonin MT1 and MT2 receptors display different molecular pharmacologies only in the G‐protein coupled state

“…Melatonin, 2‐iodo‐melatonin, 6‐chloromelatonin, 5‐HT and D 600 (+/– methoxy verapamil) were obtained from Sigma (St Louis, MO, USA); 4‐phenyl‐2‐propionamidotetraline and luzindole (2‐benzyl‐N‐acetyltryptamine) were purchased from Tocris (Bristol, UK), and 2‐bromomelatonin was purchased from Toronto Research Chemicals Inc. (Toronto, Canada). We evaluated 15 analogues of melatonin from our product library whose structures are available in Depreux et al ., ; Audinot et al ., ; Mailliet et al ., ; Audinot et al ., ; Devavry et al ., 2012a; Devavry et al ., 2012b; Legros et al ., and Ettaoussi et al ., . Compounds were dissolved in DMSO at a stock concentration of 10 mM and stored at −20°C until use.…”

Alternative Radioligands for Investigating the Molecular Pharmacology of Melatonin Receptors

“…The kinetics curves are presented in Fig. 1 We assessed a set of 24 compounds that were previously described in the literature [including 4-phenyl-2-propionamidotetraline (Dubocovich et al, 1997), luzindole (Dubocovich, 1988a), and ramelteon (Uchikawa et al, 2002)] or that were issued from our own medicinal chemistry programs (Depreux et al, 1994; Audinot et al, 2003Audinot et al, , 2008Mailliet et al, 2004;Devavry et al, 2012a,b;Ettaoussi et al, 2013;Legros et al, 2013Legros et al, , 2014 (Fig. 3) with a pK d 1 (site 1) of 10.35 6 0.03, a pK d 2 (site 2) of 9.25 6 0.13, a B max 1 (site 1) of 1.46 6 0.13 fmol·mg protein 21 , and a B max 2 (site 2) of 2.32 6 0.98 fmol·mg protein 21 (n 5 4).…”

Enhanced detection for determination of enantiomeric purity of novel agomelatine analogs byEKCusing single and dual cyclodextrin systems

“…Racemic compounds 1–5 were synthesized as previously described . 1‐P1(AS)‐(–) and 1‐P2(AS)‐(+) enantiomers were separated on Chiralpak AS column thanks to preparative HPLC.…”

“…In our continuing efforts to develop new melatoninergic ligands particularly presenting the same pharmacological profile as agomelatine, we have introduced several chemical modifications on positions known as primary targets for the agomelatine metabolism. In particular, modulation of the amide and introduction of different structural changes at the β‐position of the ethyl amido side chain . These structural modifications led to the naphthalene analogs 1–5 that possess a chiral center (Fig.…”