Synthesis of Clausenamide Isomers and Evaluation of Their Potential as Cortical Neuroplastogens

Neuroplastogens, small molecules that induce beneficial neuronal growth and plasticity, are a class of compounds emerging as new drugs for treating a range of central nervous system conditions. Clausenamide is a plasticity-promoting natural product isolated from the leaves of Clausena lansium, an evergreen native to Southeast Asia and southern China. Herein, we report an efficient synthesis of this compound by a one-pot, three-component assembly of three of the four contiguous stereogenic centers. This method enabled efficient access to six stereoisomers and one analog, which were evaluated for their ability to induce synaptogenesis in primary cortical cultures using high-content imaging. We observed a range of activities for clausenamide stereoisomers, but in general, the postsynaptic effects of the active compounds were greater than their presynaptic effects. Of the stereoisomers tested, (-)-cis-clausenamide exhibited the highest level of cortical synaptogenesis, with this effect likely being dependent on its ability to act as a 5-HT2AR partial agonist.