Xylamidine

Xylamidine is a drug which acts as an antagonist of the serotonin 5-HT_2A and 5-HT_2C receptors,^[1]^[2] and to a lesser extent of the serotonin 5-HT_1A 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-HT_2A receptor blockade such as sedation, or interfering with the central actions of 5-HT_2A receptor agonists.^[6]

Drug classPeripherally selective serotonin receptor antagonist; Serotonin 5-HT_2A receptor antagonist

ATC code

None

CAS Number

6443-50-1^Y

PubChem CID

22951

Quick facts Clinical data, Drug class ...

Xylamidine
Clinical data

Drug class	Peripherally selective serotonin receptor antagonist; Serotonin 5-HT_2A receptor antagonist
ATC code	None
Identifiers
IUPAC name N'-[2-(3-methoxyphenoxy)propyl]-2-(3-methylphenyl)ethanimidamide
CAS Number	6443-50-1^Y
PubChem CID	22951
ChemSpider	21486^Y
UNII	NY0PC84NZK
CompTox Dashboard (EPA)	DTXSID90863843
Chemical and physical data
Formula	C₁₉H₂₄N₂O₂
Molar mass	312.413 g·mol⁻¹
3D model (JSmol)	Interactive image
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)^N Key:JRYTUFKIORWTNI-UHFFFAOYSA-N^N
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Xylamidine and analogues were patented for use in combination with serotonin 5-HT_2A 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.

References

[1]
Glennon RA, Westkaemper RB (1992). "Serotonin Receptors, 5-th Ligands and Receptor Modeling". Pharmacochemistry Library. Vol. 18. Elsevier. 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]
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. doi:10.1016/S0022-3565(25)20454-2. 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.

Chemistry

Synthesis

See also

References

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