DESIGN, SYNTHESIS AND METABOLISM OF ARODYN ANALOGS

Abstract

Our research focuses on the development of kappa opioid receptor (KOR) antagonists. KOR antagonists have a variety of possible therapeutic applications; these compounds have shown anxiolytic activity, anti-depressive activity, and have potential uses in the treatment of opioid and cocaine addiction. Dynorphin A (Dyn A) is an endogenous agonist at KOR. Dyn A has been used as a lead for the development of KOR antagonists including arodyn, an acetylated Dyn A analog identified in our laboratory. Arodyn is a potent and selective KOR antagonist that has shown promise in the treatment of stress-induced relapse of cocaine seeking behavior. However, arodyn is rapidly metabolized in rat brain homogenate and slices. The objective of this research was to synthesize arodyn analogs with greater metabolic stability and to test these analogs in metabolism studies. Previous research in our laboratory had identified the sites of cleavage in arodyn and these sites were targeted for modification. Analogs with extended sequences, N-methylarginine replacements and reduced amide bond stabilizations were synthesized. In metabolism studies in washings from rat brain slices, several analogs were identified that showed increased stability over arodyn.