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Xylamidine

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Chemical compound

Pharmaceutical compound
Xylamidine
Clinical data
Drug classPeripherally selective serotonin receptor antagonist
ATC code
  • None
Identifiers
IUPAC name
  • N'--2-(3-methylphenyl)ethanimidamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H24N2O2
Molar mass312.413 g·mol
3D model (JSmol)
SMILES
  • CC1=CC(=CC=C1)CC(=NCC(C)OC2=CC=CC(=C2)OC)N
InChI
  • InChI=1S/C19H24N2O2/c1-14-6-4-7-16(10-14)11-19(20)21-13-15(2)23-18-9-5-8-17(12-18)22-3/h4-10,12,15H,11,13H2,1-3H3,(H2,20,21)
  • Key:JRYTUFKIORWTNI-UHFFFAOYSA-N
  (verify)

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 (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. Glennon RA, Westkaemper RB (1992). "Serotonin Receptors, 5-th Ligands and Receptor Modeling". Pharmacochemistry Library. Vol. 18. Elsevier. p. 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. Dave KD, Quinn JL, Harvey JA, Aloyo VJ (March 2004). "Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit". Pharmacol Biochem Behav. 77 (3): 623–629. 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. Fuller RW, Kurz KD, Mason NR, Cohen ML (June 1986). "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. doi:10.1016/0014-2999(86)90084-1. PMID 3732393.
  4. Dedeoğlu A, Fisher LA (December 1991). "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. PMID 1762059.
  5. Baker BJ, Duggan JP, Barber DJ, Booth DA (May 1988). "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. doi:10.1016/0014-2999(88)90759-5. PMID 3402534.
  6. Dave KD, Quinn JL, Harvey JA, Aloyo VJ (March 2004). "Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit". Pharmacology, Biochemistry, and Behavior. 77 (3): 623–9. doi:10.1016/j.pbb.2003.12.017. PMID 15006475. S2CID 25205829.
  7. WO 2023028086, Kruegel AC, "Combinations of peripheral 5-HT2A receptor antagonists and central 5-HT2A receptor agonists", published 2 March 2023, assigned to Gilgamesh Pharmaceuticals, Inc. 
Serotonin receptor modulators
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT37
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
Phenethylamines
Phenethylamines
Amphetamines
Phentermines
Cathinones
Phenylisobutylamines
Phenylalkylpyrrolidines
Catecholamines
(and close relatives)
Miscellaneous
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