Design, synthesis and melatoninergic potency of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines

A series of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT1 and MT2 melatonin receptor subtypes expressed in NIH 3T3 cells. Compounds with a single methylene spacer in the side chain (7) have no agonist activity, but are weak antagonists in the Xenopus melanophore assay, irrespectively of the size or shape of the R substituent (R = CH3 to c-C4H7). In contrast, compounds with two (8) or three (9) methylene spacers show partial agonist activity, though this does vary with the nature of the R substituent. Interestingly, the cyclopropane and cyclobutane R substituents, which are usually linked with antagonism, render the cyclopropanecarboxamido analog 9d and its cyclobutanecarboxamido congener 9e weak agonists. It seems, therefore, that in these compounds the R substituent constitutes a functional probe in the dynamic agonist–antagonist conformational equilibrium. One of the new molecules, antagonist 8c, exhibits a noteworthy MT2 subtype selectivity (13-fold), whereas the acetamido analog 9a (with a three methylene units spacer) also acts as an antagonist and is the only analog exhibiting MT1 selectivity (>10-fold). In contrast to the analogous N1–C7 annulated indole derivatives, recently reported, the new C1–C8 condensed isoquinolines are not all pure antagonists. Despite their modest receptor affinity at the binding site these compounds demonstrate that the nature of the response (agonist or antagonist activity) is dependent, in this case, on both the side chain spacer’s length and the size and shape of the R group.