Opioid receptors (OR), belonging to the G-Protein Coupled Receptor (GPCR) family, are comprised of κ (KOR), µ (MOR), δ (DOR) subtypes, and have been shown to play a critical role in the regulation of pain, mood, stress, anxiety, motivation, and addiction. The pharmacology of several OR ligands has been well researched, with many of the available tools displaying competing activity across the aforementioned subtypes, leading to suboptimal efficacy at the desired subtype, or dose limitations due to off target activity. Of considerable interest are KOR antagonists, which have been shown to provide anxiolytic and anti-depressant like effects in a number of models. As such, the development of new and selective KOR antagonists has been of increasing interest to the research community. Herein we will detail our medicinal chemistry efforts toward the development of novel KOR antagonists with improved physical chemical property space relative to known antagonists, the results of which ultimately led to the development of a brain penetrant tool compound with rodent in vivo efficacy.

Discovery and design of novel selective kappa opioid antagonists

255th National Meeting (2018)

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