Article
Chemistry, Physical
Moonhyuk Kwon, Joseph C. Utomo, Keunwan Park, Cameron A. Pascoe, Sorina Chiorean, Iris Ngo, Kyle A. Pelot, Cheol-Ho Pan, Seon-Won Kim, Philipp Zerbe, John C. Vederas, Dae-Kyun Ro
Summary: Research has shown that the hallucinogenic plant Salvia divinorum synthesizes neoclerodane diterpenes with regulatory effects on opioid receptors. The discovery of crotonolide G synthase (SdCS) provides a unique lead structure for drug development.
Article
Pharmacology & Pharmacy
Rink-Jan Lohman, Karnaker Reddy Tupally, Ajit Kandale, Peter J. Cabot, Harendra S. Parekh
Summary: Kappa opioid receptors have great potential as analgesic targets. Modified dynorphin peptides have been developed as safer KOP receptor agonists. These peptides showed selective and potent KOP receptor activity, improved metabolic stability, and promising analgesic efficacy in animal models.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Kelly F. Paton, Dan Luo, Anne C. La Flamme, Thomas E. Prisinzano, Bronwyn M. Kivell
Summary: This study investigated the effects of Salvinorin A analogues in a preclinical model of chemotherapy-induced neuropathic pain. The results showed that these analogues were effective in reducing pain and could be potential drugs for treating this condition.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Neurosciences
Melanie M. Pina, Dipanwita Pati, Sofia Neira, Lisa R. Taxier, Christina M. Stanhope, Alexandra A. Mahoney, Shannon D'Ambrosio, Thomas L. Kash, Montserrat Navarro
Summary: Alcohol use disorder involves multiple signaling systems and brain regions. Previous studies have shown the involvement of the insular cortex and the DYN/KOR systems in excessive alcohol use. In this study, the role of insula DYN/KOR circuit components in alcohol intake was explored. The findings revealed distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Medicine, Research & Experimental
Yuanzi Zhao, Anand A. Joshi, Jane Aldrich, Thomas F. Murray
Summary: The study explored the utility of the real-time FLIPR Membrane Potential (FMP) assay in assessing kappa opioid receptor (KOR)-induced hyperpolarization. Results showed that the FMP assay is sensitive and can effectively evaluate the potential actions and efficacy of KOR ligands. Additionally, the study demonstrated that the FMP assay is useful for detecting the potency and efficacy of KOR-selective peptides.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Plant Sciences
Renan Fernandes do Espirito-Santo, Dourivaldo Silva Santos, Pedro Santana Sales Lauria, Alyne Almeida de Lima, Lucas Silva Abreu, Josean Fechine Tavares, Marcelo Santos Castilho, Milena Botelho Pereira Soares, Cristiane Flora Villarreal
Summary: Tonantzitlolone B (TZL-B) was found to have analgesic effects in experimental animals by modulating the endogenous opioid system through increasing the transcription of PENK gene.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Neurosciences
J. D. Lorente, J. Cuitavi, L. Rullo, S. Candeletti, P. Romualdi, L. Hipolito
Summary: This study analyzed the effects of pain on negative affect in different sexes and time courses, as well as the involvement of the dynorphinergic and corticotropin releasing factor systems in these pain-related behaviors. The results showed sex and time-dependent anxiety- and anhedonia-like behaviors induced by pain in female rats. The recruitment of KOR/DYN in the NAc was identified as a key neurological substrate mediating pain-induced behavioral alterations.
Article
Neurosciences
Grace J. Lee, Shin Ae Kim, Yea Jin Kim, Seog Bae Oh
Summary: The analgesic effect induced by naloxone may be mediated by blocking facilitated kappa-opioid systems in the NAc and CeA, while KOR antagonist also reduces chronic pain behaviors.
Article
Chemistry, Medicinal
Nicholas S. Akins, Nisha Mishra, Hannah M. Harris, Narendar Dudhipala, Seong Jong Kim, Adam W. Keasling, Soumyajit Majumdar, Jordan K. Zjawiony, Jason J. Paris, Nicole M. Ashpole, Hoang Le
Summary: This study introduces a method to create compounds with dual agonism on opioid receptors. In vitro and in vivo studies show that these compounds have analgesic activity while avoiding harmful side effects.
Article
Clinical Neurology
Genis Ona, Frederic Sampedro, Sergio Romero, Marta Valle, Valle Camacho, Carolina Migliorelli, Miguel Angel Mananas, Rosa Maria Antonijoan, Montserrat Puntes, Jimena Coimbra, Maria Rosa Ballester, Maite Garrido, Jordi Riba
Summary: This study characterized the neuropharmacological effects of the highly selective KOR agonist salvinorin-A, revealing that it induces dramatic psychotomimetic effects with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ross van de Wetering, Amy Ewald, Susan Welsh, Lindsay Kornberger, Samuel E. Williamson, Bryan D. McElroy, Eduardo R. Butelman, Thomas E. Prisinzano, Bronwyn M. Kivell
Summary: This preclinical study evaluated the G-protein-biased analogue of SalA, 16-BrSalA, for its anticocaine effects and side effects, and found that it has improved pharmacokinetic profiles and fewer side effects.
Article
Neurosciences
Priscila Vazquez-Leon, Ulises Arenas-Martinez, Dafne Cordova-Maqueda, Tomas Fregoso-Aguilar, Eduardo Ramirez-San Juan, Abraham Miranda-Paez
Summary: The KOP system plays a key role in drug abuse, with Sal-A being the predominant compound isolated from Salvia divinorum. This study aimed to investigate the effects of SDE and Sal-A on alcohol intake, food consumption, and anxiety-like behavior in Wistar rats.
ACTA NEUROBIOLOGIAE EXPERIMENTALIS
(2021)
Article
Pharmacology & Pharmacy
Caroline Baynard, Thomas E. Prisinzano, Eduardo R. Butelman
Summary: This study demonstrates that a novel KOR-antagonist can rapidly produce anti-immobility effects in a model of acute stress exposure.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Pharmacology & Pharmacy
Claire Leconte, Raymond Mongeau, Florence Noble
Summary: Substance use disorders and traumatic stress-related pathologies often coexist. The KOR and DYN play a crucial role in this comorbidity, regulating the effects of stress and drug use. The DYN/KOR system is involved in anxiety, depressive symptoms, conditioned fear response, and negative reinforcement after drug use. KOR activation leads to drug-seeking behavior and cross-regulates with corticotropin-releasing factor. The sexual dimorphism of the DYN/KOR system may contribute to gender differences in patients with SUD or/and traumatic stress-related pathologies. Antagonists targeting KOR could be a promising pharmacological strategy for treating this comorbidity.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Kristina Puls, Gerhard Wolber
Summary: The natural product Salvinorin A (SalA) is a nitrogen-lacking agonist for the kappa opioid receptor (KOR) and shows potential as a new analgesic to address the opioid crisis. However, SalA has poor pharmacokinetic properties and a short duration of action, making the rational design of improved analogs necessary. In this study, the binding mode of SalA to the active state KOR was determined and the important interactions for its activity were identified. This knowledge will contribute to the understanding of KOR activation and the development of novel analgesics.
Article
Immunology
Lisa Denny, Afnan Al Abadey, Katharina Robichon, Nikki Templeton, Thomas E. Prisinzano, Bronwyn M. Kivell, Anne C. La Flamme
Summary: Nalfurafine shows potential in promoting recovery and remyelination in multiple sclerosis (MS), mediating recovery in EAE in a KOR-dependent fashion, reducing CNS infiltration, especially CD4(+) and CD8(+) T cells, and promoting a more immunoregulatory environment, while also promoting remyelination in the absence of peripheral immune cell invasion in the cuprizone demyelination model.
CLINICAL & TRANSLATIONAL IMMUNOLOGY
(2021)
Article
Neurosciences
Diana Vivian Atigari, Kelly Frances Paton, Rajendra Uprety, Andras Varadi, Amy Frances Alder, Brittany Scouller, John H. Miller, Susruta Majumdar, Bronwyn Maree Kivell
Summary: Addressing the urgent need for effective treatments for chronic pain, research suggests that mixed opioid receptor agonists targeting KOP and DOP could provide non-addictive pain medications with a wider therapeutic index. A novel compound, MP1104, demonstrates potent antinociceptive effects mediated via KOP and DOP without inducing rewarding or aversive effects.
Article
Clinical Neurology
Alison G. P. Wakeford, Alexander M. Sherwood, Thomas E. Prisinzano, Jack Bergman, Stephen J. Kohut, Carol A. Paronis
Summary: The study systematically evaluated the discriminative stimulus effects of 5 abused synthetic cathinones in nonhuman primates, suggesting that their differences in monoaminergic actions may mediate their subjective effects in humans.
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
(2021)
Article
Clinical Neurology
Eduardo R. Butelman, Caroline Baynard, Bryan D. McElroy, Thomas E. Prisinzano, Mary Jeanne Kreek
Summary: The study revealed sex differences in the responses of male and female mice to κ-agonists and short-acting κ-antagonists in the splash test of self-grooming. Males showed reduced immobility in the FST at a certain dose, while females did not; LY2795050 was able to block and reverse the locomotor depressant effects of U50,488 in both males and females.
JOURNAL OF PSYCHOPHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Ian M. Henderson, Fanxun Zeng, Nazmul H. Bhuiyan, Dan Luo, Maria Martinez, Jane Smoake, Fangchao Bi, Chamani Perera, David Johnson, Thomas E. Prisinzano, Wei Wang, George R. Uhl
Summary: This study reports a novel candidate PTPRD phosphatase inhibitor with high potency and selectivity. The compound showed good oral bioavailability and tolerance in in vivo studies, suggesting its potential role in reducing reward from addictive substances.
BIOCHEMICAL PHARMACOLOGY
(2022)
Review
Behavioral Sciences
Jeffrey M. Witkin, Arnold Lippa, Jodi L. Smith, Xiaoming Jin, Xingjie Ping, Andrew Biggerstaff, Bronwyn M. Kivell, Daniel E. Knutson, Dishary Sharmin, Kamal P. Pandey, Md Yeunus Mian, James M. Cook, Rok Cerne
Summary: This article discusses the history and recent developments of GABAkines, introducing various new compounds and steroids for the treatment of neurological and psychiatric conditions.
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
(2022)
Review
Pharmacology & Pharmacy
Martin L. Dalefield, Brittany Scouller, Rabia Bibi, Bronwyn M. Kivell
Summary: Kappa-opioid receptors have wide-ranging effects on various physiological processes and hold therapeutic potential for pain, pruritis, and other diseases. However, adverse effects limit their clinical use, highlighting the need for further development.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Fuying Li, Theresa A. Kopajtic, Jonathan L. Katz, Dan Luo, Thomas E. Prisinzano, Gregory H. Imler, Jeffrey R. Deschamps, Arthur E. Jacobson, Kenner C. Rice
Summary: This study focuses on the design and synthesis of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans as potential opioid receptor ligands. The compounds were synthesized and evaluated for their affinity and functional activity.
Article
Neurosciences
Kelly F. Paton, Sheein Hong, Andrew Biggerstaff, Bronwyn M. Kivell
Summary: This study investigates the behavioral deficits associated with cuprizone-induced demyelination in male and female mice. The results show sex differences in motor coordination and anxiety-like behaviors, providing a better understanding of the behavioral aspects of cuprizone-induced demyelination.
Article
Biochemistry & Molecular Biology
Joshua A. Lutz, Agnieszka Sulima, Eugene S. Gutman, Eric W. Bow, Dan Luo, Sophia Kaska, Thomas E. Prisinzano, Carol A. Paronis, Jack Bergman, Gregory H. Imler, Andrew T. Kerr, Arthur E. Jacobson, Kenner C. Rice
Summary: All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in search for potent MOR partial agonists. Many of these compounds exhibited nanomolar or subnanomolar potency and were fully efficacious. One compound in particular, 21, showed good potency and efficacy as a MOR partial agonist, as well as selectively activating G-protein signaling pathway. Overall, the study highlights the importance of structural modification in developing new opioids with improved analgesic properties.
Article
Biochemistry & Molecular Biology
Ross van de Wetering, Amy Ewald, Susan Welsh, Lindsay Kornberger, Samuel E. Williamson, Bryan D. McElroy, Eduardo R. Butelman, Thomas E. Prisinzano, Bronwyn M. Kivell
Summary: This preclinical study evaluated the G-protein-biased analogue of SalA, 16-BrSalA, for its anticocaine effects and side effects, and found that it has improved pharmacokinetic profiles and fewer side effects.
Article
Biochemistry & Molecular Biology
Dana R. Chambers, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Arthur E. Jacobson, Kenner C. Rice
Summary: The 5-(3-hydroxy)phenylmorphan structural class of compounds have an equatorially oriented aromatic ring and retain antinociceptive activity. The synthesized C9-alkyl diastereomers have been found to interact with opioid receptors and exhibit varying efficacy, including potent MOR agonists and a selective MOR antagonist that is more potent than naltrexone and antagonizes the EC90 of fentanyl to a greater extent.
Article
Biochemistry & Molecular Biology
Dana R. Chambers, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Alexander Goldberg, Bing Xie, Lei Shi, Carol A. Paronis, Jack Bergman, Nima Nassehi, Dana E. Selley, Gregory H. Imler, Arthur E. Jacobson, Kenner C. Rice
Summary: Four sets of diastereomeric C9-alkenyl 5-phenylmorphans with different lengths of the C9-alkenyl chain were designed to examine their effects on opioid receptors. The study found similarities and differences in their functional activities and pharmacological properties, and identified potential structures that contribute to these differences through molecular modeling.