Designer opioid receptor agonist provides pain relief without side effects

Originally Published By 2 Minute Medicine®. Reused on MPR with permission.

1. Mu opioid peptide (MOP) receptor agonists provide effective pain relief, but are associated with severe side effects such as respiratory depression, opioid-induced hyperalgesia, dependence, and abuse.

2. A bifunctional nociception/ophanin FQ peptide (NOP) and MOP agonist, AT-121, partially acts at both receptors to provide analgesic effects without inducing common opioid side effects.

Evidence Rating Level: 2 (Good)

Study Rundown: In the clinical setting, opioids are often necessary to treat severe pain; however, these medications are associated with physical dependence, abuse potential and severe side effects. The development of opioids with analgesic properties that lack these negative effects would represent a large step forward in addressing the current opioid epidemic. While several groups have tried to address this goal with various approaches such as targeting kappa opioid (KOP) and delta opioid peptide (DOP) receptors, as opposed to mu opioid receptors, there still exist no opioid agonists devoid of the risk of dependency and abuse potential.

In this study, the authors target another opioid receptor subtype, the NOP receptor, which has been shown to modulate MOP receptor activity. While NOP receptor agonists alone do not produce appropriately effective analgesia, they are able to enhance MOP agonist-induced analgesia. Moreover, they do not produce respiratory depression or reinforcing effects in primates. Based on these observations, the authors predicted that bifunctional NOP/MOP agonists would provide nonaddictive analgesia.

Bifunctional NOP/MOP receptor agonists were optimized with structure-guided drug design. The authors started with a NOP ligand, which showed modest binding affinity for the NOP receptor, but about 10-fold lower affinity and no agonist efficacy at the MOP receptor. To improve binding affinity at the MOP receptor, structure-activity relationships were explored, and certain modifications such as inclusion of cationic groups in place of nonionic cyanomethyl groups on a nitrogen of the compound were made to improve binding affinity to the NOP receptor. Five such chemical modifications of the lead chemical scaffold were made, further optimized, and their properties with explored.

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Functional efficacy and potency was determined for all compounds using a binding assay in cell membranes expressing the human NOP and MOP receptors. One compound, AT-121 displayed high potency and partial agonist efficacy both the MOP and NOP receptors. The authors note four important properties of AT-121. First, this compound produced anti-nociceptive and anti-hypersensitive effects, comparable to morphine, while being 100-fold more potent than morphine. Second, unlike oxycodone, AT-121 lacked reinforcing effects, suggesting that it is less susceptible to abuse potential. Third, AT-121 attenuated the reinforcing effects of oxycodone, suggesting that it may be a viable treatment for prescription opioid abuse. Fourth, AT-121 did not produce respiratory depression or affect cardiovascular function at 10 times the analgesic dose, suggesting that it is safer than current opioid drugs. While further testing in primate models is necessary, this rationally-designed bifunctional NOP/MOP agonist displays promise as an analgesic devoid of opioid side effects.

Click to read the study in Science Translational Medicine

Relevant Reading: Opioid receptors and addiction

In-Depth [in-vitro and in-vivo study]: This purpose of this study was to design and optimize bifunctional NOP/MOP receptor agonists. Chemical synthesis procedures, in vitro pharmacologic characterization of compounds, molecular docking and computational modeling, in vivo rodent pharmacokinetic data, and in vitro primate plasma stability data were evaluated in creation of the test compound, AT-121.

Fifteen adult male and female rhesus monkeys were used for studies with AT-121. Acute nociception was evaluated with a warm water tail-withdrawal assay, in the presence or absence of the AT-121. Doses of a NOP receptor selective antagonist and MOP receptor selective antagonist were administered 15 minutes before determination of dose-response curves to determine the NOP and MOP receptor components mediating AT-121-induced antinociception. AT-121 was found to produce full antinociception at a 0.03mg/kg dose with a 3-hour duration of action, which subsided by 6 hours.

The antiallodynic effects of AT-121 were evaluated by administering capsaicin topically via a bandage attached to the tail.  Monkeys received AT-121 or morphine on day 1 and their responses to capsaicin were measured on day 2. Systemic AT-121 administration was found to exert a dose-dependent inhibitory effect on capsaicin-induced allodynia (P < 0.05)

Monkeys with indwelling intravenous catheters and subcutaneous vascular access ports were used to determine the reinforcing effects of test compounds. Lever-pressing responses were determined with saline, cocaine, or a range of doses of AT-121. There was no significant difference between the reinforcing strengths of saline and AT-121, while oxycodone produced dose-dependent reinforcing effects.

Physiologic responses (respiration, heart rate, blood pressure, and temperature) were recorded in freely moving monkeys. For acute drug effects, data from the 30-min before drug administration were collected as baseline and then for 6 hours after intramuscular administration of AT-121 compared to a high dose of heroin. AT-121 did not cause respiratory and cardiovascular concern in primates, while heroin caused respiratory depression in a single monkey, requiring naltrexone reversal. Withdrawal signs were monitored before and after administration of an opioid antagonist. While naltrexone precipitated withdrawal signs in morphine-treated monkeys (increased respiratory rate, minute volume, heart rate, and mean arterial pressure), this was not found to be the case in AT-121 treated monkeys. Furthermore, repeated exposure to AT-121 was not found to cause opioid-induced hyperalgesia as assessed by threshold to capsaicin sensitivity over time.

Image: PD

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