Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators

The serotonin 5-HT2A receptor (5-HT2AR) and5-HT2CR localize to the brain and share overlapping signaltransduction facets that contribute to their roles in cognition, mood,learning, and memory. Achieving selective targeting of these receptorsis challenged by the similarity in their 5-HT orthosteric bindingpockets. A fragment-based discovery approach was employed to designand synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allostericmodulators (PAMs). Compound 13 (JPC0323)exhibited on-target properties, acceptable plasma exposure and brainpenetration, as well as negligible displacement to orthosteric sitesof & SIM;50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, butnot 5-HT2AR, activity at the level of the whole organismat the employed doses of 13. We discovered new selective5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explorethe biology of these vital receptors.

Automated summary

In this study, novel oleamide analogues were designed and synthesized as selective 5-HT2CR agonists or dual 5-HT2CR/5-HT2AR positive allosteric modulators using a fragment-based discovery approach. Compound 13 (JPC0323) showed on-target properties, acceptable plasma exposure and brain penetration, and negligible displacement to orthosteric sites of over 50 GPCRs and transporters. Moreover, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, indicating 5-HT2CR agonist activity at the whole organism level at the employed doses of 13. This research discovered new selective 5-HT2CR agonists and first-in-class 5-HT2CR/5-HT2AR dual positive allosteric modulators, expanding the pharmacological toolbox for exploring the biology of these important receptors.