Poster Number-62 - ADV-502, a Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: I. Discovery and Preclinical Evaluation

ADV-502, a Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: I. Discovery and Preclinical Evaluation

Purpose: As a new strategy to address the shortcomings of existing analgesic classes, a search for compounds of dual action at both the µ-opioid receptor (MOR) and the σ₁ receptor (sigma-1R) was undertaken (García et al., 2020). The rationale for seeking this particular dual action was based on the role of sigma-1R in inhibiting augmented excitability (hyperalgesia) and activity-induced plastic changes (central sensitization) secondary to sustained afferent input in chronic pain conditions (both phenomena for which opioids are generally less effective), and the fact that sigma-1R agonists have been reported to inhibit––and sigma-1R antagonists to potentiate––opioid-induced analgesia (Romero et al., 2016). Potentiation of opioid analgesia but not of opioid-related adverse events by sigma-1R blocking results in an improved safety compared to opioid monotherapy at equianalgesia (Vidal-Torres et al., 2013).

Methods: A drug discovery program was undertaken to identify a dual, bispecific drug with sigma-1R and MOR activities using a pharmacophore merging approach, i.e., combination of the two target pharmacophores MOR and sigma-1R in the same central core, which led to the discovery of ADV-502 through multiparameter optimization. Its chemical synthesis, in vitro receptor binding affinity and functionality, and in vitro and in vivo ADME profile were investigated. Specifically, ADV-502 in vivo efficacy and safety profile was compared with those of strong opioids.

Results:

The pharmacophore-merging approach discovery process led to the identification of a lead series of 4-aryl-1-oxa-4,9-diazaspiro[5.5]-undecane derivatives. ADV-502 (EST73502//WLB-73502) emerged as an optimal candidate for the treatment of pain with the correct affinity and functionality for the primary targets. It is a bispecific, dual MOR and sigma-1R ligand, selective against a panel of other 180 molecular targets (receptors, transporters, ion channels, and enzymes). Its receptor binding affinity (K_i) at human MOR and sigma-1R are 64nM and 118nM, respectively. ADV-502 is an antagonist at the sigma-1R and behaves as a partial MOR agonist at the G-protein pathway, with no/insignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signaling pathways.

In vivo testing revealed that, despite its partial MOR agonism, ADV-502 exerts full antinociceptive efficacy in several pain models in rodents, including acute nociceptive pain in the paw-pressure test (Randall-Selitto) and tail-flick test; visceral pain (both pain response and referred hyperalgesia); inflammatory (carrageenan); postoperative (paw incision): osteoarthritis (MIA knee injection); and neuropathic pain (partial sciatic nerve ligation and spared nerve injury). Potency of ADV-502 was superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, but superior to both morphine and oxycodone against neuropathic pain.

ADV-502 displays a good PK profile and low potential for DDIs (CYP interaction). Contrary to opioid comparators, ADV-502 exhibits reduced respiratory depression and GI (constipation and nausea and vomiting) MOR-related AEs, low physical dependence, and a safety profile (e.g., Irwin behavioral screen, acute and repeated-dose toxicology, genotoxicity, hERG (HEK cells) that supported its advancement to a Phase-1 clinical trial) [see the accompanying poster].

Conclusion: ADV-502 benefits from its bivalent sigma-1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy. ADV-502 shows potent analgesic activity comparable to the MOR agonist oxycodone in animal models of nociceptive, inflammatory and osteoarthritis pain, but superior to oxycodone against neuropathic pain. ADV-502 produced analgesic activity with reduced opioid-induced relevant adverse events (less inhibition of intestinal transit and respiratory depression at analgesic doses), and less naloxone-precipitated behavioral signs of opioid withdrawal. These results provide evidence that dual MOR agonism and sigma-1R antagonism may be a useful strategy for obtaining potent and safer analgesics, and they were the basis for the selection of ADV-502 as a clinical candidate for the treatment of pain [see accompanying poster].

References: García et al. (2020) J Med Chem 63:15508-26.
Vidal-Torres et al. (2013) Eur J Pharmacol 711:63–72.
Romero et al. (2016). Adv Pharmacol 75:179-215.