Date of Award
Hoang V. Le
Opioid abuse, leading to addiction and related deaths, has created a chronic epidemic in the United States for the past 30 years. This crisis has sprung from reliance on the prescription of opioid analgesics as the primary method for the management of pain in the 1990s. At that time, these drugs, specifically Purdue Pharma’s OxyContin, were marketed as non-addictive. Due to this systemic minimization of the addictive properties of opioid analgesics, as prescription rates increased, opioid-related mortality rates climbed. This epidemic continues to be pervasive, as opioid-related overdose resulted in 47,600 deaths in 2017. In addition to the opioid epidemic, there is mounting evidence of a psychostimulant addiction crisis, with psychostimulant-related overdose deaths increasing 37% from 2016 to 2017. It has been shown that there is potential for the treatment of psychostimulant and opioid addiction by antagonizing the kappa opioid receptor (KOR). The KOR is one of three opioid receptors involved in antinociception and thus plays a role in opioid addiction. Opioid analgesics acting on these G protein-coupled receptors lead to an agonistic effect. Selectivity for the KOR is of interest because it also plays a role in behavioral processes that contribute to addiction cycles, such as anxiety and depression. Antagonizing the KOR decreases symptoms of these stress states and leads to the reduction of drug reinstatement. Salvinorin A, a naturally-occurring hallucinogenic compound, is known to be a selective KOR agonist. Modifications of the structure of salvinorin A have yielded compounds found to exert antagonistic effects selectively upon the KOR. These modifications changed the topology of the ring structure in these compounds; thus we suspect that these new ring structures help the compounds bind better to the inactive or active state of the KOR. This study identifies critical interactions between salvinorin-based antagonists within the KOR, achieved by coupling structure-based drug design and computational modeling. This approach will facilitate the creation of more selective compounds for antagonizing the KOR. Docking studies performed concluded that the topology of the salvinorin scaffold determines agonistic or antagonistic functionality on the KOR.
Keane, Madeline, "Studies of Salvinorin-Based Antagonists to Elucidate Pertinent Interactions for Kappa Opioid Receptor Antagonism" (2020). Honors Theses. 1524.
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