Advances in Sulfonamide Kappa Opioid Receptor Antagonists: Structural Refinement and Evaluation of CNS Clearance

Focused modification of a sulfonamide-based kappa opioid receptor (KOR) antagonist series previously reported by this laboratory was investigated. A total of 32 analogues were prepared to explore linker replacement, constraint manipulation, and aryl group or amine substitution. All analogues were assayed for KOR antagonist activity, and the initial lead compound was assessed for in vivo CNS penetration. The most improved analogue possessed a 4-fold increase of potency (IC50 = 18.9 ± 4.4 nM) compared with the lead compound (IC50 = 83.5 ± 20 nM) from an earlier work. The initial lead compound was found to attain suitable brain levels and to possess a shorter clearance time than canonical KOR antagonists such as JDTic.