Novel Orthosteric/Allosteric Ligands of Cannabinoid Receptors: An Unexpected Pharmacological Profile

The design of dualsteric/bitopic receptor ligands as
compounds
capable of simultaneously interacting with both the orthosteric and
an allosteric binding site has gained importance to achieve enhanced
receptor specificity and minimize off-target effects. In this work,
we reported the synthesis and biological evaluation of a new series
of compounds, namely, the RF series, obtained by chemically
combining the CB1R ago-positive allosteric modulators (PAM) GAT211 with the cannabinoid receptors (CBRs) orthosteric agonist FM6b. Therefore, RF compounds were designed as
dualsteric/bitopic ligands for hCB1R with the aim
of obtaining stronger hCB1R agonists or ago-PAMs,
with improved receptor subtype selectivity and reduction of central
side effects. Unexpectedly, in vitro assays on hCB1R
indicated RF compounds were inverse agonists/antagonists,
exhibiting different profiles compared to those of parent compounds FM6b and GAT211 and, furthermore, two compounds
behaved as hCB2R PAMs. The unpredictable change in
the function of these new ligands suggests that the function of cannabinoids
is not simply predicted.