Design and Semisynthesis of Aminocannabinoids as Neurological Magic Shotguns

The design of neurological "magic shotguns" represents a modern approach toward the treatment of complex central nervous system disorders, and many natural products like cannabidiol possess distinct potential due to their unique polypharmacological profiles toward central nervous system targets. Herein, we describe the computational design, semisynthesis, and preliminary biological screening of aminergic cannabidiol derivatives as neurological magic shotguns. A small library of 22 aminergic cannabidiol derivatives were synthesized and evaluated through radioligand binding assays, revealing that these derivatives generally exhibit higher affinity toward serotonin, dopamine and sigma receptors than the parent compound. Notably, compounds <b>8d</b> and <b>8e</b> displayed significantly improved affinity toward sigma-1 receptors (K_<i>i</i> = 4.8 nM and 8.3 nM, respectively). We then established the functional behavior of compound <b>8e</b> in mouse primary hippocampal neurons through whole-cell patch clamp assays: exposure to compound <b>8e</b> potentiates <i>N</i>-methyl-d-aspartate receptors, an effect that may be reversed in the presence of a selective sigma-1 receptor antagonist. These results suggest that compound <b>8e</b> behaves as an agonist of sigma-1 receptors, thereby promoting downstream potentiation of <i>N</i>-methyl-d-aspartate receptors. Altogether, these findings provide preliminary evidence that aminergic cannabinoids, and potentially other derivatives of promiscuous natural products, may hold utility as neurological magic shotguns.