Determination of Pharmacokinetic Parameters of Subcutaneous Zyklophin by Quantitative Determination of Zyklophin in Mouse Plasma by LCMS/MS Analysis For Assessment As A Potential Therapeutic Agent In The Treatment of Cocaine Addiction

Abstract

Pharmaceutical agents targeting the μ opioid receptors (MOR) have been widely used in the treatment and management of pain. However, serious side effects and the prevalence of abuse have complicated their administration. This has increased the interest of developing pharmaceutical agents that selectively bind to the κ opioid receptors (KOR). Recent investigation has determined that KOR agonists exhibit a decreased liability for addiction as well as respiratory depression in comparison to MOR agonists. Selectively binding antagonists to the KOR have only been utilized historically as pharmacological tools. Additionally, KOR antagonists show promising potential in therapeutic treatment of depression and anxiety, as well as opiate and cocaine addiction. KOR antagonists that are metabolically stable have been shown to penetrate the CNS. However, peptide-based KOR-selective antagonists are metabolized by proteases and are expected to have a shorter activity than non-peptide KOR-selective antagonists with increased metabolic stability. Through the incorporation of unnatural amino acids as well as conformational constraints in the C terminus, zyklophin experiences increased enzymatic stability. Initial testing has shown that zyklophin crosses the blood brain barrier to antagonize the KOR in the CNS with in vivo administration and that its duration of activity after a system dose is less than 12 hours, whereas a non-peptide KOR antagonist, such as nor-BNI, exhibits duration of activity weeks after a single dose is administered. This prolonged activity complicates its use as a pharmacological tool and as a potential therapeutic agent whereby increasing the importance of peptide-based KOR antagonist. Currently, the FDA has not approved a drug for the prevention of relapse due to cocaine addiction. Peptide-based drugs have been shown to be successful pharmaceutical agents exhibiting high activity, high specificity, low toxicity, and minimal drug-drug interaction. Due to modifications of the C-terminus, zyklophin has an increased metabolic stability. Thus, zyklophin is a good lead compound for the treatment of cocaine addiction and relapse.