Substance abuse is a big problem in the US with 47,055 deaths reported due to drug overdose. Substance abuse costs the US over $600 billion annually. The opioid receptor agonist methadone and the partial agonist buprenorphine are the major agents used in opioid addiction treatment, but 40-60% of these patients relapse. Opioid receptor antagonists such as naltrexone have been shown to block relapse and curb drug craving in opiate addicts, but some severe side effects of these antagonists have been reported. Studies have shown that in mu opioid receptor (MOR) knock-out mice, the addictive/abuse liability, respiratory depression and constipation associated with opioids are abolished. Thus, blocking the MOR by opioid antagonists may lead to treatment of addiction relapse, whereas blocking the kappa opioid receptor (KOR) and delta opioid receptor (DOR) may result in side effects including depression and dysphoria. Therefore, selective MOR antagonist could be optimal for the treatment of opioid addiction. Utilizing the “message-address” concept and previous data from our lab, we have designed and synthesized a series of MOR selective antagonists. 18 compounds were synthesized and their binding affinities were determined by radioligand binding assay using Chinese hamster ovary (CHO) cells stably expressing the mouse MOR. All the compounds tested bound with high affinity (≤ 5 nM). In vitro functional studies were then conducted using the [35S]-GTPγS assay. In this assay, two compounds produced the highest stimulation of G-protein activity (60% - 88%) relative to DAMGO (a known opioid agonist). All other compounds produced low stimulation (≤ 25%) relative to DAMGO, with VZMN106 having the lowest stimulation of DAMGO. In vivo studies were conducted to test for agonism and antagonism, 10mg/kg of compounds and morphine were used. Two compounds were identified as agonists and partial agonists respectively with % maximum possible effects of 80% and 59%. In the screen for antagonism, VZMN106 was identified as the most potent antagonists and it antagonized morphine’s effect by 93%. Several compounds also antagonized morphine’s antinociception effect by more than 50%. Our molecular design strategy has been successful in producing very high affinity mu opioid receptor ligands. We have identified a MOR opioid antagonist that has the potential to be used in opioid addiction treatment.

Utilizing the message-address concept to develop selective mu opioid receptor antagonists as potential treatment of opioid addiction

253rd National Meeting (2017)

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