Mu-opioid receptor agonists that rapidly enter the brain and trigger an immediate surge of dopamine stimulating the reward pathways involved in the reinforcement behaviors underlying abuse and addiction. We hypothesized that reducing the rate of entry of a drug into the brain by modulating the physiochemical properties of a mu-opioid receptor agonist through application of our polymer conjugation technology, would provide effective analgesia for chronic pain control, but reduce the attractiveness of the drug as a target of abuse, independent of the route of administration. Following review of existing SAR, we designed, synthesized and evaluated a series of polyethylene glycol (PEG)-morphinan opioid agonist conjugates for their activity, bioavailability, and kinetics of entry into the brain, ultimately selecting NKTR-181 as the first exemplar of this new class of opioid agonists. The structure of NKTR-181 consists of a six-unit PEG chain attached to the morphinan pharmacophore, which results in a reduced rate of entry into the brain compared to conventional opioids. In pre-clinical models, NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone, but was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive ratio break point models, with behavioral effects similar to those of saline. In a dopamine microdialysis study in rat, brain uptake rates for NKTR-181, following IV administration, were 70-fold slower than for oxycodone, and a delayed and blunted dopamine response to NKTR-181 was observed when compared to oxycodone. In humans, following oral administration, the difference in the time course between plasma drug exposure and miosis indicated that the half-life of NKTR-181 brain uptake was 17.5-fold longer than that of oxycodone. Recently, NKTR-181 has demonstrated significant clinical efficacy versus placebo in patients with chronic low-back pain, was well tolerated, while demonstrating minimal drug likability, CNS adverse events and withdrawal symptoms.

NKTR-181: Separating euphoria from analgesia in a full MOR agonist

256th National Meeting (2018)

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