N-Acylaminoethyltetrahydroquinolines: A new class of melatonin receptor ligands with in vivo activity on glioblastoma

: Tetrahydroquinoline (THQ) derivatives bearing an N-acylaminoethyl side chain were investigated as a new class of potent melatonergic ligands offering opportunities for a versatile modulation of binding and pharmacological properties. These compounds were designed from N-anilinoethylamide ligands by formal closure of the N-substituent into an additional fused ring. Molecular modelling studies, including alchemical simulations, allowed to rationalize configurational and conformational aspects of ligand activity and supported the role of the THQ nucleus in the MT2 receptor selectivity observed for these compounds when compared to N-anilinoethylamide counterparts. The moderate stereoselectivity generated by substituents in position 2 of the THQ ring or at the β-position of the ethylamide chain could be ascribed to the conformational enrichment of ligand poses fitting the receptor binding site observed for the eutomer. Replacement of the methoxy group with bulkier substituents was investigated to differentially modulate intrinsic activity at the MT1 and MT2 receptor subtypes. Mixed activity, with MT1 agonist and MT2 antagonist profile, could be achieved by insertion of a 7-(2-hydroxyethoxy) group, as already observed for compound 5-HEAT. UCM1400 (4d) was more potent than 5-HEAT and emerged as a promising pharmacological tool for targeting glioblastoma. The compound exhibited in vitro antiproliferative activity on human glioma cell lines and was effective in vivo, reducing tumor growth in a U87MG orthotopic xenograft mouse model. These findings support the development of subtype-selective modulators of melatonin receptors as a promising new avenue for cancer therapy.