Chemistry:JPC0323

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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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey". Pharmaceuticals (Basel) 17 (6): 695. May 2024. doi:10.3390/ph17060695. 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. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "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. July 2023. doi:10.1021/acs.jmedchem.3c00908. PMID 37462530. 




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