Herkinorin analogues with differential β-arrestin-2 interactions

Salvinorin A is a psychoactive natural product that has been found to be a potent and selective κ opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent κ opioid receptor signaling yet leads to less receptor downregulation than observed with other κ agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin (1c), with high affinity at the μOR. We recently reported that 1c does not promote the recruitment of β-arrestin-2 to the μOR or receptor internalization. Here we describe three new derivatives of 1c (3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of β-arrestin-2 to the μOR and receptor internalization. When the important role μ opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, μ opioids derived from salvinorin A may offer a unique template for the development of functionally selective μ opioid receptor-ligands with the ability to produce analgesia while limiting adverse side effects.