Xylamidine Explained
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
Notes and References
- Book: Glennon RA, Westkaemper RB . Pharmacochemistry Library . Serotonin Receptors, 5-th Ligands and Receptor Modeling . Elsevier . 18 . 1992 . 978-0-444-88931-7 . 10.1016/b978-0-444-88931-7.50017-7 . 185–207 . 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..
- Dave KD, Quinn JL, Harvey JA, Aloyo VJ . 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 . 15006475 . 10.1016/j.pbb.2003.12.017 . 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..
- 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 .
- 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 .
- 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 .
- 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 .
- WO . 2023028086 . Combinations of peripheral 5-HT2A receptor antagonists and central 5-HT2A receptor agonists . Kruegel AC . Gilgamesh Pharmaceuticals, Inc. . 2 March 2023 .