Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor

Salahuddin

et al. 2023

ACS Chem. Neurosci.

Self Cite

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 the 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 a 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 persistent pharmacodynamic activities can hinder the ability to reverse unanticipated side effects immediately. Herein, we report our studies of the lead selective, salvinorin-based KOR antagonist (1) as well as nor-BNI on C57BL/6N male 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 KOR antagonists.

Section: Methodsmentioning

confidence: 99%

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-Based Antagonists and Kappa Opioid Receptor

Salahuddin

et al. 2023

ACS Chem. Neurosci.

Self Cite

“…Compound 2 exhibited hydrogen bonding with Y148 3.33 , K233 5. 58 , and W318 7.35 , as well as hydrophobic interactions with other residues (Figure S4C). Compound 6 exhibited hydrogen bonding with K233 5.58 and W318 7.35 , as well as π-stacking interactions with Y326 7.42 and W293 6.48 (Figure S4D).…”

Section: Insights Into the Binding To Mormentioning

confidence: 99%

“…Compounds 2 and 6 possessed additional hydrogen bonding and hydrophobic interactions with other residues, such as Y148 3.33 , K233 5. 58 , and W318 7.35 (for 2), and K233 5.58 , W318 7.35 , Y326 7.42 , and W293 6.48 (for 6). These additional interactions are likely responsible for the higher binding affinities of 2 and 6 to MOR, compared to that of 1.…”

Section: Insights Into the Binding To Mormentioning

confidence: 99%

See 1 more Smart Citation

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

Mohammed

et al. 2022

Preprint

The kappa opioid receptor (KOR) is involved in the regulation of both 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), are shown to halt depressive and anxiety-related disorders, which are the common side effects of withdrawal that can lead to the relapse of 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. Additionally, their persisted pharmacodynamic activities can hinder the ability to reverse unanticipated side effects instantly. 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 1 to be 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. Additionally, we identified pertinent interactions between 1 and KOR via computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulations, to gain insights into the design of future selective, potent, and short-acting salvinorin-based antagonists.

“…injection of 1 and underwent anesthetized, transcardial perfusion with PBS either 5, 15, 30, 60, 120, or 360 min later (n=3/time-point) as described. 62 Brain, liver, dorsal spinal cord, and plasma were collected at each time-point as described below.…”

Section: Pharmacokinetic Assessment Ofmentioning

confidence: 99%

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

Mohammed

et al. 2022

Preprint

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 persistent pharmacodynamic activities can hinder the ability to reverse unanticipated side effects immediately. Herein we report our studies of 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.