Today’s unrelenting opioid crisis has resulted in massive deaths, sweeping debilitation, and significant economic impact. The widespread opioid misuse is the original cause for this opioid epidemic. However, over 25 million American adults are currently affected by daily pain in the absence of non-addictive analgesic drugs. Possessing analgesic effects, kappa opioid receptor (KOR) agonists are lack of abuse liability, making them potential targets for developing pain relievers. Nalfurafine is an anti-pruritus drug and the only KOR agonist approved on the market. We designed and conducted a systematic structure-activity relationship (SAR) study of nalfurafine in order to develop non-addictive analgesics. We explored stereoselective reductive amination synthetic routes and “one-pot” methods to prepare the critical intermediates. Then we prepared and tested the target compounds for their <i>in vitro</i> binding affinities and functional activities at opioid receptors. Our further <i>in vivo</i> experimental data demonstrated the analgesic effects of the compounds, three out of which showed much higher potencies than morphine. Future work includes studies to confirm non-addictive features of these analgesic agents and pharmacokinetic characterization.

Systematic structure-activity relationships study of nalfurafine for developing non-addictive analgesics

ACS Spring Meeting 2021

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