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 8d and 8e displayed significantly improved affinity toward
sigma-1 receptors (Ki = 4.8 nM and 8.3
nM, respectively). We then established the functional behavior of
compound 8e in mouse primary hippocampal neurons through
whole-cell patch clamp assays: exposure to compound 8e potentiates N-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 8e behaves as an agonist of sigma-1 receptors, thereby promoting downstream
potentiation of N-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.