Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Production Centers Network (MLPCN)
Grant Number: 1X01DA026208-01
Assay Provider: Dr. Lawrance Barak , Duke University, Durham NC

Drug addiction is a disease originating in the central nervous system that produces compulsive behaviors despite the negative consequences that may result. Major addictive drugs of abuse include components of tobacco, opiates, marijuana, ethanol, cocaine, and derivatives of amphetamines. While the addictive behaviors produced by these substances may be generally similar, the drugs act at different receptor sites in the brain. Recent studies have shown that opioid receptors play a role regulating the addictive behaviors of other receptors that interact with illicit and legal substances of abuse. Opioid receptors are composed of multiple subtypes whose contributions to addictive behaviors are not fully delineated. Moreover, different compounds acting at a single receptor type may produce dissimilar behaviors due to variations in their chemical structures. Thus, both for delineating the biology and signaling ability of each receptor and for developing novel therapies, it would be desirable to identify multiple small molecule ligands that target a given receptor subtype. This entails expanding the chemical space about each of the receptors as variations in receptor conformations due to distinct ligand structures affect receptor signaling behaviors, and consequently physiological responsiveness. Morphine is a prime example of an opioid ligand with distinctive signaling properties.

The specific aim of this project is to identify subtype specific small molecule agonists of the human kappa opioid receptor (KOR). These compounds can be optimized to provide the pharmacological means to precisely control the signaling of their specific target receptor subtype. This work thus provides the addiction field both novel research tools and potential therapeutic scaffolds.

This AID summarizes SBCCG's probe development efforts to identify antagonists of the kappa opioid receptor (KOR).

From the primary HTS and subsequent hit confirmation (AID 1778) several hit compounds were identified. Hits were clustered into scaffolds and SAR studies were performed on compounds from several scaffolds reconfirming potency (AID 2285). Antagonist activity was further confirmed for these compounds via image-based high content assays (AID 2348). Compounds were further tested for selectivity against the related delta (AID 2357) and mu opioid receptors (AID 2420). A novel scaffold was identified as a KOR antagonist, with CID3342390 (ML140) representing a very potent and selective member of the chemical series. This antagonist compound was later nominated to probe candidacy status.

As second novel more potent antagonist (120 nM by DiscoveRx) for the kappa opioid (KOP) receptor that is >267-fold selective over the mu(MOP) and the delta(DOP) opioid receptors is CID44665680 (ML190). Importantly, this probe and its analogs represent a novel chemical class compared to current literature antagonists and our previously submitted probe, ML140. Accordingly, this probe and its analogues may serve as interesting tools to advance addiction research. Additionally, this new chemotype is less complicated compared to known KOP receptor antagonist compounds. The structure contains no stereochemical centers and the short, versatile synthetic route enables both the synthesis of potential analogs and the production of the compound on larger scale.



Details of protocols, compound structures, and results from the original assays can be found in PubChem at the respective AIDs listed below.

Please see pertinent AIDs: 1778, 1966, 2136, 2285, 2348, 2356, 2357, 2420, 2478, 2491, 2495, 2498, 434981, 463105, 488819, 488826, 488831, 488842, 488925, 488935

Probe molecules are defined as the positives of this assay and assigned a score of 100. Compound SIDs 87218794 and 88442997 have been identified as probe molecules.

Grant Number: 1X01DA026208-01