Kappa-opioid receptors (KORs) play a key role in several autoimmune disorders and neurological diseases. Located within the central nervous system and periphery, activated KORs suppress the demyelinating T Cells that cause multiple sclerosis. However, KORs that are activated in the brain can lead to the negative side effects normally associated with opioids, namely dysphoria, sedation, and diuresis. If the agonist cannot cross the blood-brain barrier and remains in the periphery, these side effects can be avoided. As a component of a broader research program studying small molecule activators of KORs, this report focuses on the synthesis of a quinoline-based conformationally-restricted KOR agonist for the treatment of multiple sclerosis. A nine-step synthetic route, including a Boekelheide rearrangement and a rhodium catalyzed enantioselective hydrogenation, is reported for the lead compound. Characterization studies are currently underway to verify the structure of the final compound, as well as a large scale synthesis.<br/>

Synthesis of conformationally restricted kappa-opioid receptor agonists

2019 Spring National Meeting

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