Towards the development of mixed MT(1)-agonist/MT(2)-antagonist melatonin receptor ligands

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 MT1 and MT2 receptors. Fromthis series of N-acyltryptamines the 2-bromo derivative (5c) 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 MT1 agonist/MT2 antagonist. Some other full agonists for both melatonin receptors which exhibit similar or increased affinity relative to that of melatonin were obtained.