Isoquinolinones That Bind to the Kappa Opioid Receptor

University of Kansas
posted on 08/25/2009

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Kappa opioid receptor (KOR) antagonists have proven efficacious for a number of medical uses that include treatment of cocaine addition, depression, or other central nervous system indications (for a review, see: Metcalf MD, Coop A. Kappa Opioid Antagonists: Past Successes and Future Prospects. AAPS Journal. 2005; 7(3): E704-E722). A great deal of work toward discovering new KOR antagonists has focused on two classical opioid chemotypes: morphine derivatives and neuropeptides. Although existing agents have been invaluable in determining proof of concept for the uses noted above, known agents generally suffer from one or more of the following drawbacks: poor potency, unsatisfactory selectivity for the KOR over the other opioid receptors (mu (MOR) or delta (DOR)), or poor pharmacokinetic properties. New chemical compounds that would address these limitations would be of great interest to the drug addiction research community and other biological scientists. The present disclosure reveals an entirely new chemotype of KOR weak partial agonists. These compounds are highly potent (one to three-digit nanomolar range) and highly selective (KOR/MOR and KOR/DOR ratios > 150). In those cases that have been studied so far, the compounds are weak partial agonists, meaning that they would be expected to have similar in vivo effects to pure antagonists. Furthermore, the compounds are all nicely behaved “drug-like” structures that have all of the structural features typically associated with potential drug development. The compounds themselves are highly amenable to chemical synthesis and diversification; most members of the class are expected to be readily available on the multigram scale necessary for preclinical development. We expect that these chemical syntheses could readily be scaled up to any degree warranted. Finally, many analogs of the structures have been prepared to date and many more should be readily available. This means that there will be ample opportunity to identify analogs that have appropriate pharmacokinetic properties necessary for drug development.

Such compounds are of possible interest for the treatment of drug addiction or depression, among numerous other clinical applications.

The synthetic approach to these molecules has proven very versatile and a major advantage in this technology is the ability to synthesis a variety of analogs of these agents.