N‐Acetyl‐5‐arylalkoxytryptamine Analogs: Probing the Melatonin Receptors for MT₁‐Selectivity

Abstract

A series of melatonin analogs obtained by the replacement of the ether methyl group with larger arylalkyl and aryloxyalkyl substituents was prepared in order to probe the melatonin receptors for MT(1) -selectivity. The most MT(1) -selective agents 11 and 15 were substituted with a Ph(CH(2) )(3) or a PhO(CH(2) )(3) group. Compounds 11 and 15 displayed 11.5-fold and 11-fold higher affinity for the MT(1) receptors than for the MT(2) subtype. Interestingly, in our binding assay 11 and 15 have shown considerably higher MT(1) -affinity and selectivity than the reference ligand, the dimeric agomelatine 1a.

Update on melatonin receptors: IUPHAR Review 20

“…N ‐acetyl‐ O ‐phenoxypropyl serotonin is a full agonist obtained by exchange of the methoxy group of melatonin with an O(CH 2 ) 3 OPh moiety. Although it shows only 10‐fold binding preference toward hMT 1 receptors, its MT 1 –MT 2 receptor binding ratio and hMT 1 receptor affinity were higher than that for the MT 1 receptor‐selective reference compound S 26131 that was retested under the same experimental conditions (Markl et al, ). A 140‐fold MT 1 receptor selectivity could be attained by introduction of two fluorine atoms into the N ‐acetyl group of agomelatine.…”

Alternative Radioligands for Investigating the Molecular Pharmacology of Melatonin Receptors

“…Few diverse tools have been developed for MLT molecular pharmacology studies (Markl et al, 2011), such as subtypespecific agonists or antagonists, or biased agonists (Devavry et al, 2012b;Legros et al, 2014). We further screened our compounds (Yan et al, 2008) to find various types of ligands that are amenable to chemical conversion to iodinated and radioactive derivatives.…”

New Radioligands for Describing the Molecular Pharmacology of MT1 and MT2 Melatonin Receptors

“…Such a discovery would help broaden our understanding of this system for which almost no molecules have been reported [13]. It thus follows that such a molecule would then be labeled in order to obtain new ligands.…”