Novel difluoroacetamide analogues of agomelatine and melatonin: probing the melatonin receptors for MT₁selectivity

Abstract

The difluoroacetamide analogue of the standard MT1-selective ligand, the dimeric (CH2)3-linked agomelatine, shows higher affinity and selectivity toward MT1receptors than the parent compound.

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

“…Halogenated amide analogues of melatonin ( 424 ) and agomelatine ( 426 ) have revealed interesting structure–activity relationships that indicate the importance of the fluorination pattern on binding affinity (Table ). The CF 3 amide 429 derived from 426 shows reduced affinity but similar receptor selectivity, while the CH 2 F homologue 427 exhibits 10-fold selectivity for the MT 2 receptor subtype. In contrast, the CHF 2 amide is 10-fold selective for MT 1 receptor and retains the potency of 426 , a profile analogous to that of the urea 431 , while the balanced profile and reduced potency of the CHCl 2 amide 430 illustrates the importance of selecting the correct halogen …”

Virtual discovery of melatonin receptor ligands to modulate circadian rhythms

“…The two receptors are established drug targets for aligning circadian phase in disorders of sleep 5 , 6 and depression 7 , 1 – 4 , 8 , 9 . Despite their importance, few if any in vivo active MT 1 selective ligands have been reported 2 , 8 , 10 – 12 , hampering both the understanding of circadian biology and the development of targeted therapeutics. We docked over 150 million virtual molecules against an MT 1 crystal structure, prioritizing structural fit and chemical novelty.…”

Update on melatonin receptors: IUPHAR Review 20

“…The resulting difluoroagomelatine shows high hMT 1 receptor binding ( K i = 0.03 nM) and is a non‐selective MT 1 –MT 2 receptor full agonist (Ettaoussi et al, ). Very recently, tetrafluoro S26131, the difluoroacetamide analogue of S 26131, has been reported to show higher affinity and selectivity toward hMT 1 receptors than the parent ligand (Zlotos et al , ).…”