Alleviation of cocaine withdrawal and pertinent interactions between salvinorin-based antagonists and kappa opioid receptor

Authors: AKINS, NICHOLAS - University Of Mississippi; MOHAMMED, SALAHUDDIN - University Of Mississippi; PANDEY, PANKAJ - University Of Mississippi; Kim, Seong; MAHDI, FAKHRI - University Of Mississippi; KHAN, MD IMADADUL - University Of Mississippi; MOSS, EMAYA - University Of Mississippi; WORTH, CHARLIE - University Of Mississippi; KEANNE, MADELINE - University Of Mississippi; CHITTIBOYINA, AMAR - University Of Mississippi; DOERKSEN, ROBERT - University Of Mississippi; PARIS, JASON - University Of Mississippi; LE, HOANG - University Of Mississippi

Submitted to: ACS Chemical Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/2/2023
Publication Date: 2/16/2023
Citation: Akins, N.S., Mohammed, S.F., Pandey, P., Kim, S., Mahdi, F., Khan, M.H., Moss, E., Worth, C.J., Keanne, M.M., Chittiboyina, A.G., Doerksen, R.J., Paris, J.J., Le, H.V. 2023. Alleviation of cocaine withdrawal and pertinent interactions between salvinorin-based antagonists and kappa opioid receptor. ACS Chemical Neuroscience. https://doi.org/10.1021/acschemneuro.2c00806.
DOI: https://doi.org/10.1021/acschemneuro.2c00806

Interpretive Summary: In 2019, cocaine as an opioid was responsible for 16,000 American deaths (19% of all overdose deaths in the United States). In 2020, over 5 million Americans (almost 2% of the population) reported current cocaine use. Research on cocaine dependence has been widely carried out, but effective medications have not been produced. A cocaine epidemic is imminent; thus, the need for new therapeutics for cocaine use disorder is urgent. The kappa opioid receptor (KOR) is involved in regulating both the reward and mood processes. Long-acting KOR antagonists, such as norbinaltorphimine (nor-BNI), JDTic, and 5'-guanidinonaltrindole (GNTI), have been used as prototypical therapeutic agents for various neuropsychiatric conditions, including depression, anxiety, and substance abuse disorders. However, these prototypical KOR antagonists induce selective KOR antagonism delayed by hours and highly prolonged. Moreover, the in vivo showed that the brain uptakes of these compounds were very slow, and their presence in the brain was persistent and still detectable at one week. This report showed novel salvinorin-based opioid receptors as KOR antagonists. Especially, 1 showed reducing spontaneous cocaine-withdrawal behaviors, comparable to nor-BNI. Moreover, 1 produced anti-anxiety-like behavior in the light-dark transition test that was not observed with nor-BNI. The pharmacokinetic profile of 1 is promising with accumulation in the central compartment evident after systemic administration. These results support the study of selective, short-acting KOR antagonists for the treatment of psychostimulant withdrawal and the associated negative mood states that contribute to relapse. Furthermore, the study identified pertinent interactions between 1 and KOR via computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulations, to gain insight into the design of future selective, potent, and short-acting salvinorin-based antagonists.

Technical Abstract: The kappa opioid receptor (KOR) is involved in the regulation of both the reward and mood processes. Recent reports find that the use of drugs of abuse increases the production of dynorphin and overall activation of KOR. Long-acting KOR antagonists, such as norbinaltorphimine (nor-BNI), JDTic, and 5'-guanidinonaltrindole (GNTI), have been shown to stop depressive and anxiety-related disorders, which are the common side effects of withdrawal that can lead to the relapse in drug use. Unfortunately, these prototypical KOR antagonists are known to induce selective KOR antagonism that is delayed by hours and extremely prolonged, and their use in humans comes with serious safety concerns because they possess a large window for potential drug-drug interactions. Furthermore, their persisted pharmacodynamic activities can hinder the ability to reverse unanticipated side effects immediately. Herein we report our studies on the lead selective, salvinorin-based KOR antagonist (1) as well as nor-BNI on C57BL/6N mice for spontaneous cocaine withdrawal. Assessment of pharmacokinetics showed that 1 is a short-acting compound with an average half-life of 3.75 h across different compartments (brain, spinal cord, liver, and plasma). Both 1 (5 mg/kg) and nor-BNI (5 mg/kg) were shown to reduce spontaneous withdrawal behavior in mice, with 1 producing additional anti-anxiety-like behavior in a light-dark transition test (however, no mood-related effects of 1 or nor-BNI were observed at the current dosing in an elevated plus maze or a tail suspension test). Our results support the study of selective, short-acting KOR antagonists for the treatment of psychostimulant withdrawal and the associated negative mood states that contribute to relapse. Furthermore, we identified pertinent interactions between 1 and KOR via computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulations, to gain insight into the design of future selective, potent, and short-acting salvinorin-based antagonists.