Towards the Development of Mixed MT₁‐Agonist/MT₂‐Antagonist Melatonin Receptor Ligands

Abstract

Herein we report attempts to optimize the pharmacological properties of 5-(2-hydroxyethoxy)-N-acetyltryptamine (5-HEAT), a melatonin receptor ligand previously described by us. Several 5-substituted and 2,5-disubstituted N-acyltryptamines were synthesized and evaluated in vitro for the human cloned MT(1) and MT(2) receptors. From this series of N-acyltryptamines the 2-bromo derivative (5 c) retains the interesting efficacy profile of 5-HEAT and shows increased melatonin receptor affinities; it represents one of the first examples of a high-affinity MT(1) agonist/MT(2) antagonist. Some other full agonists for both melatonin receptors which exhibit similar or increased affinity relative to that of melatonin were obtained.

Use of Bromine and Bromo-Organic Compounds in Organic Synthesis

“…Several 5substituted and 2,5-disubstituted N-acyltryptamines were synthesized for this purpose. 1055 From this series of Nacyltryptamines, the 2-bromo derivative retains an interesting efficacy profile. For this experiment they used PTAB for the bromination of various substrates.…”

“…Spadoni et al reported attempts to optimize the pharmacological properties of 5-(2-hydroxyethoxy)- N -acetyltryptamine, a melatonin receptor ligand. Several 5-substituted and 2,5-disubstituted N -acyltryptamines were synthesized for this purpose . From this series of N -acyltryptamines, the 2-bromo derivative retains an interesting efficacy profile.…”

Melatonin Receptor Agonists: New Options for Insomnia and Depression Treatment

“…Compounds with subnanomolar affinity and modest selectivity for the MT 1 subtype (MT 2 /MT 1 selectivity ratios approximately ranging from 20 to 40) have been obtained when a 4‐phenylbutyl group was introduced at the C2‐position of the bicyclic scaffold, as exemplified by compounds 29 [117], 30 [118] and 31 [119] in Figure 3. By replacement of the methoxy group of MLT with a 5‐hydroxyethoxy substituent interesting compounds were obtained, some of which ( 32 [120], 33 [121]) have similar binding affinity for the two receptor subtypes, but functional selectivity on GTPγS binding, as they displayed MT 1 agonist and MT 2 antagonist properties. Taken together, all these results have led to the hypothesis that MT 1 selectivity is favored by replacement of the 5‐methoxy group by a larger substituent.…”

A Novel Synthesis of the Antidepressant Agomelatine

“…In order to minimize the number of reaction steps and to achieve the best possible overall yield, we have chosen a one-pot Ra-Ni hydrogenation/acetylation procedure previously reported for the reduction of nitriles to give directly the N-acetylated product. 11 We were pleased to find that aldoxime 8 could be converted into agomelatine using Ra-Ni hydrogenation in the presence of acetic anhydride in an excellent 98% yield.…”