MAPPING THE MELATONIN RECEPTOR .3. DESIGN AND SYNTHESIS OF MELATONIN AGONISTS AND ANTAGONISTS DERIVED FROM 2-PHENYLTRYPTAMINES

Three series of 2-phenyltryptamides were prepared as melatonin analogu es to investigate the nature of the binding site of the melatonin rece ptor in chicken brain and in Xenopus laevis melanophore cells. The 5-m ethoxy-2-phenyltryptamides (6a-j) have high binding affinities for the chicken brain receptor, in some cases (6a-d) greater than that for me latonin, confirming and extending the work of Spadoni et al., and act as agonists in the Xenopus melanophore assay. Analogues lacking the 5- methoxyl group (2a-n) had a considerably lower affinity for the chicke n brain receptor. In the Xenopus melanophore assay the compounds acyla ted on nitrogen by an alkyl group (2a-d) were agonists whereas the com pounds acylated on nitrogen by an alicyclic group (2a-d) were antagoni sts. Introducing a methyl group at N-1 (7) led to an increase in bindi ng affinity in the chicken brain assay, whereas introducing an ethyl g roup (13) led to a decrease in binding affinity. A methyl substituent at the beta-position of the 3-amidoethane side chain (8, 11) also led to an increase in the binding affinity. The only analogue acylated on nitrogen with an alkyl group (acetyl) which showed antagonist activity was 9, which has a beta-methoxymethyl side chain. In the absence of t he 5-methoxyl group the methoxymethyl function may cause the molecule to bind in a different configuration so that it is no longer able to a ctivate the receptor. All of these observations are in agreement with a model of melatonin at the receptor site in which the 3-amidoethane s ide chain is in a conformation close to the 5-methoxyl group.