The present invention is an entirely new chemotype of KOR weak partial agonists.
A great deal of work toward discovering new KOR antagonists has focused on two classical opioid chemotypes: morphine derivatives and neuropeptides. 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 or delta), or poor pharmacokinetic properties.
The present invention is 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). The compounds have all of the structural features typically associated with potential drug development. They 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. These chemical syntheses could readily be scaled up to any degree warranted. Multiple analogues have been made which provides ample opportunity to identify analogs that have appropriate pharmacokinetic properties necessary for drug development.
Compounds can be used for treatment of drug addiction (preventing, inhibiting, or relieving the disease), depression or other central nervous system indicators. The compounds can be bioactive with regard to interacting and modulating opioid receptors and may be agonist and/or antagonist.
The synthetic approach to these molecules has proven very versatile and a major advantage in this technology is the ability to synthesize a variety of analogs of these agents. With such a selection, compounds can be broad spectrum agents or more targeted. Another benefit is the ability to scale up the reaction. The individual enantiomers for each compound can be separated.