Cocaine abuse is a serious relapsing condition that affects both individuals and public health. While cocaine is a major illegal drug of abuse, with almost 5 million cocaine users in the US, there are currently no medications approved for the treatment of cocaine abuse and addiction. Relapse to drug seeking behavior after a period of abstinence is a major challenge in the long term treatment of cocaine abuse, with both stress and exposure to cocaine contributing to relapse. Thus there is a pressing need to identify and develop new compounds as potential therapeutics for the prevention of relapse to cocaine abuse. The kappa opioid receptor (KOR) system modulates dopaminergic pathway function, and ligands for KOR have demonstrated potential as therapeutics for cocaine abuse. KOR agonists have been shown to prevent cocaine-seeking behavior and cocaine-primed relapse of drug-seeking behavior following abstinence. Additionally, KOR selective antagonists can prevent stress-induced reinstatement of cocaine-seeking behavior that is mediated by the release of endogenous KOR agonists and activation of KOR. However, until recently, no single opioid ligand had been reported that is capable of preventing both of these important triggers for reinstatement of drug seeking behavior. This competitive renewal focuses on optimizing the structure of a novel mixed opioid agonist/KOR antagonist ligand that we have demonstrated can prevent both cocaine- and stress-induced reinstatement of cocaine-seeking behavior after oral administration. Recent studies with this lead compound demonstrate the importance of its balanced opioid activity in the minimization of potential side effects such as sedation and conditioned place preference or aversion. Additional studies indicate it exerts its effects on the opioid system in vivo through a novel combination of both direct and indirect mechanisms. Our optimization efforts will focus on improving the pharmacokinetic properties of the lead compound to enhance its oral activity while retaining its balanced opioid agonist/KOR antagonist profile. The proposed multidisciplinary research will be performed by a highly qualified team of researchers with synergistic expertise, and consists of three specific aims: 1) synthesis of analogs of the lead compound to enhance its oral activity, 2) in vitro pharmacological and pharmacokinetic studies of the analogs to optimize these important parameters, and 3) evaluation of the compounds in vivo for their opioid receptor profile and their ability to prevent cocaine-seeking behavior. This translational research program is expected to produce optimized analogs that can be advanced into the later stages of preclinical development as potential treatments for cocaine addiction and relapse.
Ligands for kappa opioid receptors (KOR) have potential as maintenance medications to prevent relapse to cocaine-seeking behavior in abstinent subjects. A novel ligand possessing distinct KOR agonist and antagonist activity has been identified that can prevent both cocaine- and stress-induced reinstatement of cocaine-seeking behavior representing two critical factors that can trigger relapse. This proposal focuses on optimizing this lead compound for pharmacological activity after oral administration and generating candidates for development as potential treatments for cocaine addiction and relapse.
|Aldrich, J V; Senadheera, S N; Ross, N C et al. (2014) Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour. Br J Pharmacol 171:3212-22|
|Aldrich, Jane V; Senadheera, Sanjeewa N; Ross, Nicolette C et al. (2013) The macrocyclic peptide natural product CJ-15,208 is orally active and prevents reinstatement of extinguished cocaine-seeking behavior. J Nat Prod 76:433-8|
|Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J et al. (2013) The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting * opioid receptor antagonism in the CNS after oral administration. Br J Pharmacol 169:426-36|
|Walker, Brendan M; Valdez, Glenn R; McLaughlin, Jay P et al. (2012) Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol 46:359-70|
|Ross, Nicolette C; Reilley, Kate J; Murray, Thomas F et al. (2012) Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting ? opioid receptor antagonism. Br J Pharmacol 165:1097-108|
|Kelamangalath, Lakshmi; Dravid, Shashank M; George, Joju et al. (2011) ?-Opioid receptor inhibition of calcium oscillations in spinal cord neurons. Mol Pharmacol 79:1061-71|
|Aldrich, Jane V; Kulkarni, Santosh S; Senadheera, Sanjeewa N et al. (2011) Unexpected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208. ChemMedChem 6:1739-45|
|Aldrich, Jane V; Patkar, Kshitij A; McLaughlin, Jay P (2009) Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action. Proc Natl Acad Sci U S A 106:18396-401|
|Aldrich, Jane V; McLaughlin, Jay P (2009) Peptide kappa opioid receptor ligands: potential for drug development. AAPS J 11:312-22|