Figure 3.

Biased signaling by CB1 allosteric ligands: (A) orthosteric ligands, represented in yellow, promote G-protein signaling and β-arrestin recruitment in a balanced manner, stimulating conformational changes important for both; (B) ORG27569, in purple, inhibits G-protein signaling and stimulates β-arrestin signaling, whether alone or in the presence of an orthosteric ligand, generating β-arrestin-biased signaling. This occurs due to inhibition of TMH6 movement and stimulation of TMH7/Hx8 movement, respectively; (C) pregnenolone, in magenta, inhibits β-arrestin signaling in the presence of an orthosteric ligand, generating G-protein-biased signaling. This occurs due to inhibition of TMH7/Hx8 movement while allowing TMH6 movement; (D) GAT1601, in dark red, stimulates G-protein signaling and β-arrestin2 recruitment to a smaller extent but not β-arrestin1 recruitment, generating G-protein-biased signaling. This occurs due to the facilitation of TMH6 movement.