The present invention is an entirely new chemotype of KOR weak partial agonists.
The invention is a method for antagonizing kappa opioid receptors (KOR) present in tissue in vitro or in vivo. KORs are widely distributed in the brain, spinal cord, and in pain neurons. As such, KORs have been investigated for therapeutic potential in the treatment of addiction. Small molecules have been used to decrease physical and mental conditions associated with addiction; however, many small molecules with bioactivity have negative side effects due to the ability of the molecule to interaction with the proper receptor associated with the addiction and non-targeted receptors. Furthermore, the use of selective non-peptide KOR antagonist in vivo is often complicated by unusually long activity. KU researchers have discovered that cyclic tetrapeptides are KOR antagonist that can be used in therapeutic applications for treating, inhibiting, and/or preventing drug addiction, drug use, or drug seeking behavior in a subject.
Cyclic tetrapeptides can be used to treat subjects with a history of drug addiction to cocaine, alcohol, amphetamines, methamphetamines, nicotine, opiate, or combinations thereof. Additionally, these tetrapeptides can be useful for treating, inhibiting and/or preventing stress-induced drug seeking behavior.
Peptide KOR antagonist can exhibit shorter duration of action, are metabolically stable and can cross the blood-brain barrier. The inventors have created a line of cyclic tetrapeptide KOR antagonists and derivatives that are at least 3-fold more effective than the parent compound, CJ 15,208.