2-SUBSTITUTED 5-METHOXY-N-ACYLTRYPTAMINES - SYNTHESIS, BINDING-AFFINITY FOR THE MELATONIN RECEPTOR, AND EVALUATION OF THE BIOLOGICAL-ACTIVITY

A series of a-substituted 5-methoxy-N-acyltryptamines was synthesized and their affinity for the melatonin receptor, isolated from whole qua il brains, was tested in a succession of in vitro ligand-receptor bind ing experiments, using 2-[I-125] iodomelatonin as a labeled ligand. Op timization of the C-2 substituent and the N-acyl group resulted in com pounds having picomolar affinity for the receptor (vs nanomolar affini ty for melatonin). In two tests for evaluation of the biological activ ity (effects on the spontaneous firing activity of single neurons in t he rabbit parietal cortex in situ, and the Syrian hamster gonadal regr ession model in vivo) most of the analogs behaved as agonists. Isoprop yl substitution at C-2 alone, or concomitantly with cyclopropyl substi tution at the N-acyl position, resulted in much lower affinity and wea ker biological effect, or lack of activity in the latter case. Of inte rest are the compounds 4d (R = phenyl, R(1) = CH3) and 4g (R = phenyl, R(1) = cyclopropyl), which expressed high affinity for the receptor a nd apparent antagonistic activity under the conditions of the experime ntal model employed, though the analog 4g (R = phenyl, R(1) = cyclopro pyl) seemingly was a weak antagonist and in situ expressed mixed activ ity in the higher concentration range. Cyclopropyl substitution at the N-acyl position inevitably resulted in lower affinity for the recepto r and weaker biological activity. These data demonstrate that the N-ac etyl group is important for both affinity and agonist biological activ ity. The substituents at C-2 are crucial for the affinity of the compo und for the receptor and can be utilized to create putative high-affin ity agonists or antagonists.