New, Melatonin Receptors Selective 2-Phenyl/C5-Substituted Ν-Acylated Tryptamines

A series of substituted 2-phenylindoles with a reduced C3-side chain length were synthesized and tested for affinity, selectivity, and apparent efficacy to the MT1 and MT2 melatonin receptors. The new indole melatonin analogues were prepared by condensing the requisite anilines with the appropriate acetophenones, followed by cyclization of the produced imines, and then C3-side chain functionalization. Affinity and apparent efficacy were determined by competition binding of the analogues for 2-[¹²⁵I]-iodomelatonin for the MT1 and MT2 melatonin receptors stably expressed in heterologous mammalian cells, in the absence and presence of GTP. All the compounds show selectivity for the MT2 receptor, as a result of the combination of the C-2 phenyl substitution and the reduction of the C3-NHCOR spacer length to one methylene unit. Compounds 8a-10a showed higher affinity and selectivity for the hMT2 receptor, with compound Ν-[(5-methoxy-2-phenyl-1Η-indol-3-yl)methyl]butyramide (10a) showing the highest affinity. Modifications to the C5-substituent as well as substituting the C-2 phenyl ring lead to MT2-binding analogues with a decrease in both affinity and selectivity compared with the 8-10a series, as well as their agonist efficacy.