Xylamidine Explained

Xylamidine is a drug which acts as an antagonist at the 5HT_2A receptor, and to a lesser extent at the 5HT_1A receptor. It does not cross the blood–brain barrier, which makes it useful for blocking peripheral serotonergic responses like cardiovascular^{[1] [2]} and gastrointestinal effects,^[3] without producing the central effects of 5HT_2A blockade such as sedation, or interfering with the central actions of 5HT_2A agonists.^[4]

Synthesis

Xylamidine is an amidine which serves as a serotonin inhibitor. This agent is prepared by alkylation of 3-methoxyphenol (m-methoxyphenol) with α-chloropropionitrile, KI and potassium carbonate in MEK 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 HCl, the synthesis is completed. Alternately, one can react primary amine # with m-tolylacetamidine under acid catalysis to produce xylamidine.

Notes and References

1. Fuller RW, Kurz KD, Mason NR, Cohen ML . Antagonism of a peripheral vascular but not an apparently central serotonergic response by xylamidine and BW 501C67 . European Journal of Pharmacology . 125 . 1 . 71–7 . June 1986 . 3732393 . 10.1016/0014-2999(86)90084-1 .
2. Dedeoğlu A, Fisher LA . Central and peripheral injections of the 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, modify cardiovascular function through different mechanisms . The Journal of Pharmacology and Experimental Therapeutics . 259 . 3 . 1027–34 . December 1991 . 1762059 .
3. Baker BJ, Duggan JP, Barber DJ, Booth DA . Effects of dl-fenfluramine and xylamidine on gastric emptying of maintenance diet in freely feeding rats . European Journal of Pharmacology . 150 . 1–2 . 137–42 . May 1988 . 3402534 . 10.1016/0014-2999(88)90759-5 .
4. Dave KD, Quinn JL, Harvey JA, Aloyo VJ . Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit . Pharmacology, Biochemistry, and Behavior . 77 . 3 . 623–9 . March 2004 . 15006475 . 10.1016/j.pbb.2003.12.017 . 25205829 .