Xylamidine


Xylamidine is a drug which acts as an antagonist of the serotonin 5-HT2A and 5-HT2C receptors, and to a lesser extent of the serotonin 5-HT1A receptor. The drug does not cross the blood–brain barrier and hence is peripherally selective, which makes it useful for blocking peripheral serotonergic responses like cardiovascular and gastrointestinal effects, without producing the central effects of 5-HT2A receptor blockade such as sedation, or interfering with the central actions of 5-HT2A receptor agonists.
Xylamidine and analogues were patented for use in combination with serotonin 5-HT2A receptor agonists like serotonergic psychedelics in 2023.

Chemistry

Synthesis

Xylamidine is an amidine. It is prepared by alkylation of 3-methoxyphenol with α-chloropropionitrile, potassium iodide, and potassium carbonate in butanone to give #, which is in turn reduced with lithium aluminium hydride to give the primary amine #. When # is treated with m-tolylacetonitrile in the presence of anhydrous hydrochloric acid, the synthesis is completed. Alternately, one can react primary amine # with m-tolylacetamidine under acid catalysis to produce xylamidine.