Cinnamamides as structural analogs and antagonists of serotonin

Abstract

Cinnamamides with aminoalkyl groups on the amide nitrogen were conceived as structural analogs of serotonin which would act as antimetabolites of it. Several such amides were synthesized and tested for antiserotonin activity on the isolated rat uterus and in living animal. All such amides that were tested acted as antagonists of the hormone. When the structural analogy to serotonin was increased by introduction of a meta-methoxyl group in the. benzene ring, antiserotonin potency was increased considerably. A further increase in potency was achieved by introduction of a benzyl group on the amide nitrogen. The most active cinnamamide proved to be more active as a serotonin antagonist in the rat uterus assay than the previously known and highly potent 1-benzyl-2-methyl-5-methoxytryptamine (BAS), and was much easier to synthesize. It was, however, less active than BAS in the in-vivo assay that was used. The compounds were not antagonistic toward acetylcholine or bradykinin on rat uterus. It was suggested that some previously known cinnamamides may owe some of their pharmacological activity (e.g. local anesthetic) to their ability to act as antimetabolites of serotonin.