Chemistry:Xylamidine

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Xylamidine is a drug which acts as an antagonist of the serotonin 5-HT2A and 5-HT2C receptors,[1][2] 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[3][4] and gastrointestinal effects,[5] without producing the central effects of 5-HT2A receptor blockade such as sedation, or interfering with the central actions of 5-HT2A receptor agonists.[6]

Xylamidine and analogues were patented for use in combination with serotonin 5-HT2A receptor agonists like serotonergic psychedelics in 2023.[7]

Chemistry

Synthesis

Xylamidine is an amidine. It is prepared by alkylation of 3-methoxyphenol (m-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.

See also

References

  1. ↑ "Serotonin Receptors, 5-th Ligands and Receptor Modeling". Pharmacochemistry Library. 18. Elsevier. 1992. pp. 185–207. doi:10.1016/b978-0-444-88931-7.50017-7. ISBN 978-0-444-88931-7. "Various polycyclic agents such as butaclamol, mianserin, cyproheptadine, pizotyline bind at 5-HT2 receptors with high affinity. These agents are not selective and bind with comparable affinty either at other populations of 5-HT receptors or at other neurotransmitter receptors. Other, structurally unique agents have also been investigated including cinanserin and xylamidine. The latter compound has seen application as a peripheral 5-HT2 antagonist in that it does not readily penetrate the blood-brain barrier; however, xylamidine binds equally well at 5-HTIC and 5-HT2 receptors. See references 3 and 5 for additional information on these types of agents." 
  2. ↑ "Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit". Pharmacol Biochem Behav 77 (3): 623–629. March 2004. doi:10.1016/j.pbb.2003.12.017. PMID 15006475. "Systemic administration of the peripheral 5-HT2A/2C antagonist xylamidine [...] First, systemic injections of the peripherally acting 5-HT2A/2C receptor antagonist xylamidine were employed to study its effects on head bobs and body shakes produced by systemic injections of DOI.". 
  3. ↑ "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. doi:10.1016/0014-2999(86)90084-1. PMID 3732393. 
  4. ↑ "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. doi:10.1016/S0022-3565(25)20454-2. PMID 1762059. 
  5. ↑ "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. doi:10.1016/0014-2999(88)90759-5. PMID 3402534. 
  6. ↑ "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. doi:10.1016/j.pbb.2003.12.017. PMID 15006475. 
  7. ↑ Kruegel AC, "Combinations of peripheral 5-HT2A receptor antagonists and central 5-HT2A receptor agonists", WO patent 2023028086, published 2 March 2023



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