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JPC0323

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JPC0323
Clinical data
Other namesJPC-0323; N-(1,3-Dihydroxy-2-(hydroxymethyl)propan-2-yl)oleamide
Drug classSerotonin 5-HT2C and 5-HT2A receptor positive allosteric modulator
ATC code
  • None
Identifiers
  • (Z)-N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]octadec-9-enamide
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC22H43NO4
Molar mass385.589 g·mol−1
3D model (JSmol)
  • CCCCCCCC/C=C\CCCCCCCC(=O)NC(CO)(CO)CO
  • InChI=1S/C22H43NO4/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-21(27)23-22(18-24,19-25)20-26/h9-10,24-26H,2-8,11-20H2,1H3,(H,23,27)/b10-9-
  • Key:JLFKELVBPUSMGW-KTKRTIGZSA-N

JPC0323, also known as N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)oleamide, is a dual serotonin 5-HT2C and 5-HT2A receptor positive allosteric modulator related to oleamide.[1][2] It showed negligible affinity for roughly 50 other targets and did not bind to the orthosteric sites of these receptors.[1][2] The drug does not affect the serotonin 5-HT2B receptor.[1][2]

JPC0323 showed favorable pharmacokinetic properties in preclinical research.[1][2] It produced hypolocomotion in a serotonin 5-HT2C receptor-dependent but not serotonin 5-HT2A receptor-dependent manner in rats, suggesting that it might be a preferential serotonin 5-HT2C receptor positive allosteric modulator in vivo.[1][2] The drug was not assessed in terms of head-twitch response, an animal behavioral proxy of psychedelic effects.[2] It is unknown whether it might have hallucinogenic effects via serotonin 5-HT2A receptor potentiation, but its developers speculated that it might have reduced potential in this regard compared to orthosteric agonists.[2]

JPC0323 was derived as an analogue of the fatty acid amide oleamide and was first described in the scientific literature by 2023.[1][2] It was described as a "first-in-class" dual serotonin 5-HT2C and 5-HT2A receptor positive allosteric modulator.[2]

See also

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References

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  1. ^ a b c d e f Brunetti L, Francavilla F, Leopoldo M, Lacivita E (May 2024). "Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey". Pharmaceuticals (Basel). 17 (6): 695. doi:10.3390/ph17060695. PMC 11206742. PMID 38931362. Several compounds of this series showed significant efficacy at 1 nM in improving 5-HT-mediated calcium efflux. Interestingly, while some of them were selective PAMs of 5-HT2CR, others were described as dual 5-HT2AR/5-HT2CR PAMs. None of these compounds were reported as PAMs of 5-HT2BR. A full characterization was conducted for dual PAM JPC0323 (Figure 6), which evoked a 44% increase in maximum 5-HT-induced Ca2+ intake and also showed negligible displacement at orthosteric binding sites of a number of GPCRs and transporters and exhibited favorable pharmacokinetic parameters. In rats, JPC0323 suppressed spontaneous ambulation in a 5-HT2CR-dependent manner, suggesting that the compound has a preference for 5-HT2CR over 5-HT2AR [75].
  2. ^ a b c d e f g h i Chen J, Garcia EJ, Merritt CR, Zamora JC, Bolinger AA, Pazdrak K, Stafford SJ, Mifflin RC, Wold EA, Wild CT, Chen H, Anastasio NC, Cunningham KA, Zhou J (July 2023). "Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators". J Med Chem. 66 (14): 9992–10009. doi:10.1021/acs.jmedchem.3c00908. PMC 10853020. PMID 37462530.


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