From LP2 to 2S-LP2: discovery of a biased dual-target mu/delta opioid receptor agonist for pain management

Opioid analgesics, such as morphine, elicit analgesic effects primarily through mu opioid receptor (MOR), whose activation determines not only analgesia but also unwanted side effects. Although indispensable for the management of acute severe pain, classical analgesics are unsuccessful for inflammatory and neuropathic pain treatment. Multitarget MOR/delta opioid receptor (DOR) agonists, showing synergic antinociceptive activity with low side-effects induction in preclinical models, represent a strategy to overcome the default in chronic pain treatment.

In this context, we identified the dual-target ligand LP2 characterized by high MOR (K_i= 1.08 nM) and DOR (K_i= 6.6 nM) affinity coupled to an agonist profile versus these receptors (IC₅₀^MOR= 21.5 nM and IC₅₀^DOR= 4.4 nM). In tail flick test, LP2 produced a long-lasting antinociception naloxone-reversed (ED₅₀of 0.9 mg/kg i.p.). Building upon these evidences, our efforts were focused on demonstrating whether the LP2 multitarget profile could be useful for persistent pain states. Thus, LP2 was evaluated in an animal model of inflammatory and neuropathic pain.

Moreover, both 2R- and 2S-diastereoisomers of LP2 were synthesized in order to investigate the role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold in drug-opioid receptor interaction. Their pharmacological profile was compared each other and with LP2.

Specifically, 2S-LP2 showed an increased antinociceptive effect than LP2 consistent with the in vitrofunctional profile. Moreover, 2S-LP2 resulted a biased MOR/DOR agonist with functional selectivity for G-protein signaling and reduced β-arrestin 2 recruitment, an effectiveness profile in chronic pain conditions management.