Development of kappa opioid receptor agonists for non-addictive pain relief

The development of non-addictive opioids for pain relief remains a current unmet medical need emphasized by the exponential increase in opioid involved overdose deaths since the late 1990s. While most typical opioids, such as morphine and fentanyl, exert their analgesic and euphoric effects via activation of the μu opioid receptor, there is increasing evidence that activation of the κ opioid receptor offers another approach to pain relief and anti-itch properties without the addictive side effect profile. Unfortunately, development of kappa opioid receptor agonists has been hampered by a different dose-limiting side effect, dysphoria. Recent research has shown that selective activation of the G protein signaling pathway over the βarrestin signaling pathway, a phenomenon known as biased signaling, can untangle the desired and undesired effects of kappa opioid receptor activation. Our lab has previously developed triazole 1.1 as a lead probe to investigate this hypothesis. Armed with triazole 1.1, we aimed to extend our understanding of the structure activity relationships in terms of both G protein signaling potency and G protein bias. Design and synthesis of 3,4,5-trisubstutited 1,2,4-triazoles, tertiary amides, and 1,2,5-trisubsitued imidazoles have informed these relationships. Importantly, we have designed single digit nanomolar analogues with bias factors over 70. These new compounds are important for furthering our understanding of G protein-biased kappa opioid receptor agonists.