Selective KOP Receptor Agonists: Probe 1 & Probe 2

The κ opioid receptors (KOR) provide desirable substrates for targeted therapy and unraveling pathways responsible for mediating addictive behavior. Kappa opioid agonists offer a means to modulate the effects of stimulant drugs. However, there currently are no available approved agents or compounds for these purposes. Thus, the specific aim of this project was to identify subtype specific small molecule agonists of the human KOR. Such agonists might be useful in elucidating different signaling modalities for kappa receptors, but more importantly, they might also be partial agonists that will facilitate the discovery of new molecular scaffolds for kappa antagonists. In this report, we describe the discovery and optimization of two novel agonists for the KOR, the small molecular probes ML139 (CID-5236771) and ML138 (CID-44601470), each of which are greater than 100-fold selective over the mu-(µ) and delta (δ) opioid subtype receptors. Furthermore, these probes and their analogs represent novel chemical classes compared to current literature agonists, with potentially unique pharmacology that may serve as interesting tools to advance addiction research.