A new melatonin receptor ligand with mt(1)-agonist and MT2-antagonist properties

It has been difficult, so far, to obtain melatonin analogs possessing high selectivity for the respective melatonin receptors, mt, and MT2. In the pre sent work, we report the synthesis and pharmacological characterization of a new compound N-{2-[5-(2-hydroxyethoxy)-1H-indol-3-yl)] ethyl} acetamide o r 5-hydroxyethoxy-N-acetyltryptamine (5-HEAT). To assess the activity of th e compound, the following tests were performed: affinity determination for the high- and low-affinity receptor states (2-[I-125]iodomelatonin binding) , potency and intrinsic activity in inducing G protein activation ([S-35]GT P gammaS binding assay). 5-HEAT showed little selectivity for the mt(1) rec eptor, with pK(i) values of 7.77 for mt(1) and 7.12 for the MT2 receptors, respectively. 5-HEAT was able to differentiate between the high- and the lo w-affinity receptor states in the mt(1) but not in the MT2 receptor. 5-HEAT induced a high level of G protein activation when acting through the mt(1) receptor, with a relative intrinsic activity of 0.92. On the contrary, it elicited only minimal MT2 receptor-mediated G protein activation, with a re lative intrinsic activity of 0.16, and was also able to inhibit the melaton in-induced MT2 receptor-mediated G protein activation, with a pK(B) value o f 7.4. In conclusion, it appears that 5-HEAT possesses very different effic acies at the two melatonin receptors, behaving as a full melatonin receptor agonist at the mt(1) and as an antagonist/weak partial agonist at the MT2 receptor. Therefore, it is a promising ligand for use in functional studies aimed at distinguishing between the effects mediated by the different mela tonin receptors in the human.