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Cannabidiol Attenuates Seizures and Social Deficits in a Mouse Model of Dravet Syndrome
Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome Joshua S. Kaplana, Nephi Stellaa,b,1, William A. Catteralla,1,2, and Ruth E. Westenbroeka,1 aDepartment of Pharmacology, University of Washington, Seattle, WA 98195; and bDepartment of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195 Contributed by William A. Catterall, September 7, 2017 (sent for review July 3, 2017; reviewed by Lori L. Isom, Daniele Piomelli, and Peter C. Ruben) Worldwide medicinal use of cannabis is rapidly escalating, despite 17). Previous work showed that DS symptoms result from the loss- limited evidence of its efficacy from preclinical and clinical studies. of-function of Nav1.1 channels, which selectively reduces sodium Here we show that cannabidiol (CBD) effectively reduced seizures current and excitatory drive in many types of GABAergic inter- and autistic-like social deficits in a well-validated mouse genetic neurons (13, 14, 18–20). Accordingly, targeting the Scn1a mutation model of Dravet syndrome (DS), a severe childhood epilepsy disorder to Nav1.1 channels in forebrain GABAergic interneurons re- caused by loss-of-function mutations in the brain voltage-gated capitulated the DS phenotype and established that hypoexcitability sodium channel NaV1.1. The duration and severity of thermally in- of these interneurons is sufficient to cause the epileptic phenotype duced seizures and the frequency of spontaneous seizures were sub- (21) and autistic-like behaviors (16) observed in DS mice. In con- stantially decreased. Treatment with lower doses of CBD also trast, targeting the Scn1a mutation to excitatory neurons ameliorates improved autistic-like social interaction deficits in DS mice. -
Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer
cancers Review Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer Viktoriia Cherkasova, Olga Kovalchuk * and Igor Kovalchuk * Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada; [email protected] * Correspondence: [email protected] (O.K.); [email protected] (I.K.) Simple Summary: In recent years, multiple preclinical studies have shown that changes in endo- cannabinoid system signaling may have various effects on intestinal inflammation and colorectal cancer. However, not all tumors can respond to cannabinoid therapy in the same manner. Given that colorectal cancer is a heterogeneous disease with different genomic landscapes, experiments with cannabinoids should involve different molecular subtypes, emerging mutations, and various stages of the disease. We hope that this review can help researchers form a comprehensive understanding of cannabinoid interactions in colorectal cancer and intestinal bowel diseases. We believe that selecting a particular experimental model based on the disease’s genetic landscape is a crucial step in the drug discovery, which eventually may tremendously benefit patient’s treatment outcomes and bring us one step closer to individualized medicine. Abstract: Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in Citation: Cherkasova, V.; Kovalchuk, critical need, and based on recent experimental data, cannabinoids could become excellent candidates. O.; Kovalchuk, I. Cannabinoids and This review covered known experimental studies regarding the effects of cannabinoids on intestinal Endocannabinoid System Changes in inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous Intestinal Inflammation and disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and Colorectal Cancer. -
NIH Public Access Author Manuscript Drug Alcohol Depend
NIH Public Access Author Manuscript Drug Alcohol Depend. Author manuscript; available in PMC 2015 October 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Drug Alcohol Depend. 2014 October 1; 143: 251–256. doi:10.1016/j.drugalcdep.2014.08.004. Effects of the cannabinoid CB1 receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine- seeking behavior in rats* Li Jinga,b, Yanyan Qiua, Yanan Zhangc, and Jun-Xu Lia aDepartment of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA bDepartment of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China cResearch Triangle Institute, Research Triangle Park, North Carolina, USA Abstract Background—Cannabinoid CB1 receptors play an essential role in drug addiction. Given the side effect profiles of orthosteric CB1 antagonism, new strategies have been attempted to modulate this target, such as CB1 receptor allosteric modulation. However, the effect of CB1 allosteric modulation in drug addiction is unknown. The present study examined the effects of the CB1 receptor allosteric modulator ORG27569 on the reinstatement of cocaine- and methamphetamine- seeking behavior in rats. Methods—Rats were trained to self-administer 0.75 mg/kg cocaine or 0.05 mg/kg methamphetamine in 2-hr daily sessions for 14 days which was followed by 7 days of extinction sessions in which rats responded on the levers with no programmed consequences. On reinstatement test sessions, rats were administered ORG27569 (1.0, 3.2, 5.6 mg/kg, i.p.) or SR141716A (3.2 mg/kg, i.p.) 10 min prior to re-exposure to cocaine- or methamphetamine-paired cues or a priming injection of cocaine (10 mg/kg, i.p.) or methamphetamine (1 mg/kg, i.p.). -
Synthetic Cannabinoids (60 Substances) A) Classical Cannabinoid
Synthetic cannabinoids (60 substances) a) Classical cannabinoid OH H OH H O Common name Chemical name CAS number Molecular Formula HU-210 3-(1,1’-dimethylheptyl)-6aR,7,10,10aR-tetrahydro-1- Synonym: 112830-95-2 C H O hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol 25 38 3 11-Hydroxy-Δ-8-THC-DMH b) Nonclassical cannabinoids OH OH R2 R3 R4 R1 CAS Molecular Common name Chemical name R1 R2 R3 R4 number Formula rel-2[(1 S,3 R)-3- hydroxycyclohexyl]- 5- (2- methyloctan- 2- yl) CP-47,497 70434-82-1 C H O CH H H H phenol 21 34 2 3 rel-2[(1 S,3 R)-3- hydroxycyclohexyl]- 5- (2- methylheptan- 2- yl) CP-47,497-C6 - C H O H H H H phenol 20 32 2 CP-47,497-C8 rel-2- [(1 S,3 R)-3- hydroxycyclohexyl]- 5- (2- methylnonan- 2- yl) 70434-92-3 C H O C H H H H Synonym: Cannabicyclohexanol phenol 22 36 2 2 5 CAS Molecular Common name Chemical name R1 R2 R3 R4 number Formula rel-2[(1 S,3 R)-3- hydroxycyclohexyl]- 5- (2- methyldecan- 2- yl) CP-47,497-C9 - C H O C H H H H phenol 23 38 2 3 7 rel-2- ((1 R,2 R,5 R)-5- hydroxy- 2- (3- hydroxypropyl)cyclohexyl)- 3-hydroxy CP-55,940 83003-12-7 C H O CH H H 5-(2- methyloctan- 2- yl)phenol 24 40 3 3 propyl rel-2- [(1 S,3 R)-3- hydroxy-5,5-dimethylcyclohexyl]- 5- (2- Dimethyl CP-47,497-C8 - C H O C H CH CH H methylnonan-2- yl)phenol 24 40 2 2 5 3 3 c) Aminoalkylindoles i) Naphthoylindoles 1' R R3' R2' O N CAS Molecular Common name Chemical name R1’ R2’ R3’ number Formula [1-[(1- methyl- 2- piperidinyl)methyl]- 1 H-indol- 3- yl]- 1- 1-methyl-2- AM-1220 137642-54-7 C H N O H H naphthalenyl-methanone 26 26 2 piperidinyl -
Positive Allosteric Modulators (Pams) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects, and Neuropathic Pain
Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2021 Investigating Cannabinoid Type-1 Receptor (CB1R) Positive Allosteric Modulators (PAMs) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects, and Neuropathic Pain Jayden Elmer Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Behavioral Neurobiology Commons, Behavior and Behavior Mechanisms Commons, Medicinal and Pharmaceutical Chemistry Commons, Nervous System Diseases Commons, and the Pharmacology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/6777 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. 2021 Investigating Cannabinoid Type-1 Receptor (CB1R) Positive Allosteric Modulators (PAMs) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects and Neuropathic Pain Jayden A. Elmer Investigating Cannabinoid Type-1 Receptor (CB1R) Positive Allosteric Modulators (PAMs) in Mouse Models of Overt Cannabimimetic Activity, Subjective Drug Effects and Neuropathic Pain A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University By Jayden Aric Elmer Bachelor of Science, University of Virginia, 2018 Director: Dr. Aron Lichtman, Professor, Department of Pharmacology & Toxicology; Associate Dean of Research and Graduate Studies, School of Pharmacy Virginia Commonwealth University Richmond, Virginia July 2021 Acknowledgements I would first like to extend my gratitude towards the CERT program at VCU. The CERT program opened the doors for me to get involved in graduate research. -
Cannabinoid Receptor Cannabinoid Receptor
Cannabinoid Receptor Cannabinoid Receptor Cannabinoid receptors are currently classified into three groups: central (CB1), peripheral (CB2) and GPR55, all of which are G-protein-coupled. CB1 receptors are primarily located at central and peripheral nerve terminals. CB2 receptors are predominantly expressed in non-neuronal tissues, particularly immune cells, where they modulate cytokine release and cell migration. Recent reports have suggested that CB2 receptors may also be expressed in the CNS. GPR55 receptors are non-CB1/CB2 receptors that exhibit affinity for endogenous, plant and synthetic cannabinoids. Endogenous ligands for cannabinoid receptors have been discovered, including anandamide and 2-arachidonylglycerol. www.MedChemExpress.com 1 Cannabinoid Receptor Antagonists, Agonists, Inhibitors, Modulators & Activators (S)-MRI-1867 (±)-Ibipinabant Cat. No.: HY-141411A ((±)-SLV319; (±)-BMS-646256) Cat. No.: HY-14791A (S)-MRI-1867 is a peripherally restricted, orally (±)-Ibipinabant ((±)-SLV319) is the racemate of bioavailable dual cannabinoid CB1 receptor and SLV319. (±)-Ibipinabant ((±)-SLV319) is a potent inducible NOS (iNOS) antagonist. (S)-MRI-1867 and selective cannabinoid-1 (CB-1) receptor ameliorates obesity-induced chronic kidney disease antagonist with an IC50 of 22 nM. (CKD). Purity: >98% Purity: 99.93% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg, 50 mg 2-Arachidonoylglycerol 2-Palmitoylglycerol Cat. No.: HY-W011051 (2-Palm-Gl) Cat. No.: HY-W013788 2-Arachidonoylglycerol is a second endogenous 2-Palmitoylglycerol (2-Palm-Gl), an congener of cannabinoid ligand in the central nervous system. 2-arachidonoylglycerol (2-AG), is a modest cannabinoid receptor CB1 agonist. 2-Palmitoylglycerol also may be an endogenous ligand for GPR119. -
P.1.G.070 PHARMACOLOGICAL BLOCKADE of GPR55 in the ANTERIOR CINGULATE CORTEX REDUCES FORMALIN-EVOKED NOCICEPTIVE BEHAVIOUR in RATS Bright N
P.1.g.070 PHARMACOLOGICAL BLOCKADE OF GPR55 IN THE ANTERIOR CINGULATE CORTEX REDUCES FORMALIN-EVOKED NOCICEPTIVE BEHAVIOUR IN RATS Bright N. Okine 1, 3, Gemma McLaughlin 1 , Michelle Roche 2, 3 , David P. Finn 1, 3 1Pharmacology and Therapeutics, 2Physiology, School of Medicine, 3Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland Galway, University Road, Galway, Ireland Introduction Results Intra-ACC administration of the GPR55 antagonist Intra-ACC administration of the GPR55 •The G-protein coupled receptor 55 reduced second phase formalin-evoked antagonist reduced ERK (GPR55), is a putative novel cannabinoid nociceptive behaviour in rats phosphorylation in the ACC receptor expressed throughout the central nervous system (CNS), including key brain regions such as the anterior cingulate cortex (ACC)1 which is associated with the ERK 1 ERK 2 cognitive-affective components of pain2. 1.2 150 150 Vehicle •Pharmacological modulation of GPR55 in CID 100 100 the rat periaqueductal grey (PAG) affects 0.9 * nociceptive responding in rodents3. vehicle of 50 vehicle of 50 * expressed as a % a as expressed % a as expressed ERK 42 (phospho/total) 42 ERK (phospho/total) 44 ERK 0.6 0 0 •The PAG is a key component of the descending pain pathway, an endogenous pain modulatory system, and is subject to 0.3 Total ERK (1/2) modulation by higher brain centres including Vehicle CID the ACC. However, the role of. GPR55 150 p=0.06 Composite pain scorepain Composite 0.0 signalling in the ACC in pain processing is unknown. 0-5 100 6-10 11-1516-2021-2526-3031-3536-4041-4546-5051-5556-60 Vehicle 50 total 42+44 / total 42+44 •This study investigated the effects of direct Time bins (5 mins) / 44+42 Phospho administration of the selective GPR55 0 antagonist, CID16020046, into the ACC, on Figure 1. -
A Cannabinoid CB1 Receptor Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects
NPP-15-0045 A Cannabinoid CB1 Receptor Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with no Psychoactive Effects 1 †Bogna M. Ignatowska-Jankowska, 5, †Gemma L. Baillie, 3Steven Kinsey, 3Molly Crowe, 1Sudeshna Ghosh, 1 Robert Allen Owens, 1M. Imad Damaj, 1Justin Poklis, 4Jenny L. Wiley, 2Matteo Zanda, 2Chiara Zanato, 2Iain R. Greig, 1††Aron H. Lichtman, 5†† Ruth A. Ross. 1 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA; 2 School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; 3 Department of Psychology, West Virginia University, Morgantown, WV, USA; 4 Research Triangle Institute, Research Triangle Park, NC, USA; 5 Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto. †Joint first authors. ††Joint corresponding authors Running Title: CB1 Allosteric Modulation 1 ABSTRACT The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ9-tetrahydrocannabinol (THC) and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2- phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 3 potentiated binding of [ H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [35S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB1 cells. -
Icrs2015 Programme
TH 25 ANNUAL SYMPOSIUM OF THE INTERNATIONAL CANNABINOID RESEARCH SOCIETY WOLFVILLE NOVA SCOTIA JUNE 28 - JULY 3, 2015 TH 25 ANNUAL SYMPOSIUM OF THE INTERNATIONAL CANNABINOID RESEARCH SOCIETY WOLFVILLE JUNE 28 – JULY 3, 2015 Symposium Programming by Cortical Systematics LLC Copyright © 2015 International Cannabinoid Research Society Research Triangle Park, NC USA ISBN: 978-0-9892885-2-1 These abstracts may be cited in the scientific literature as follows: Author(s), Abstract Title (2015) 25th Annual Symposium on the Cannabinoids, International Cannabinoid Research Society, Research Triangle Park, NC, USA, Page #. Funding for this conference was made possible in part by grant 5R13DA016280-13 from the National Institute on Drug Abuse. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Sponsors ICRS Government Sponsors National Institute on Drug Abuse Non- Profit Organization Sponsors Kang Tsou Memorial Fund 2015 ICRS Board of Directors Executive Director Cecilia Hillard, Ph.D. President Stephen Alexander, Ph.D. President- Elect Michelle Glass, Ph.D. Past President Ethan Russo, M.D. Secretary Steve Kinsey, Ph.D. Treasurer Mary Abood, Ph.D. International Secretary Roger Pertwee, D . Phil. , D . S c. Student Representative Tiffany Lee, Ph.D. Grant PI Jenny Wiley, Ph.D. Managing Director Jason Schechter, Ph.D. 2015 Symposium on the Cannabinoids Conference Coordinators Steve Alexander, Ph.D. Cecilia Hillard, Ph.D. Mary Lynch, M.D. Jason Schechter, Ph.D. -
Appendix-2Final.Pdf 663.7 KB
North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project Appendix 2 – Analytical methodologies Overview Urine samples were analysed using three methodologies. The first methodology (General Screen) was designed to cover a wide range of analytes (drugs) and was used for all analytes other than the synthetic cannabinoid receptor agonists (SCRAs). The analyte coverage included a broad range of commonly prescribed drugs including over the counter medications, commonly misused drugs and metabolites of many of the compounds too. This approach provided a very powerful drug screening tool to investigate drug use/misuse before and whilst in prison. The second methodology (SCRA Screen) was specifically designed for SCRAs and targets only those compounds. This was a very sensitive methodology with a method capability of sub 100pg/ml for over 600 SCRAs and their metabolites. Both methodologies utilised full scan high resolution accurate mass LCMS technologies that allowed a non-targeted approach to data acquisition and the ability to retrospectively review data. The non-targeted approach to data acquisition effectively means that the analyte coverage of the data acquisition was unlimited. The only limiting factors were related to the chemical nature of the analyte being looked for. The analyte must extract in the sample preparation process; it must chromatograph and it must ionise under the conditions used by the mass spectrometer interface. The final limiting factor was presence in the data processing database. The subsequent study of negative MDT samples across the North West and London and the South East used a GCMS methodology for anabolic steroids in addition to the General and SCRA screens. -
A Selective Antagonist Reveals a Potential Role of G Protein-Coupled
JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 JPETThis Fast article Forward. has not been Published copyedited and on formatted. May 2, The 2013 final as version DOI:10.1124/jpet.113.204180 may differ from this version. JPET #204180 Title Page A selective antagonist reveals a potential role of G protein-coupled receptor 55 in platelet and endothelial cell function Julia Kargl*, Andrew J Brown, Liisa Andersen, Georg Dorn, Rudolf Schicho, Maria Waldhoer and Akos Heinemann Downloaded from Primary laboratory of origin: Institute for Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria jpet.aspetjournals.org Affiliation: Institute for Experimental and Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria at ASPET Journals on September 26, 2021 (J.K., L.A., G.D., R.S., M.W., A.H.); Screening and Compound Profiling, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK (A.J.B); current address: Hagedorn Research Institute, Novo Nordisk A/S, 2820-Gentofte, Denmark (M.W.) 1 Copyright 2013 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on May 2, 2013 as DOI: 10.1124/jpet.113.204180 This article has not been copyedited and formatted. The final version may differ from this version. JPET #204180 Running Title Page Characterization of a GPR55 antagonist *Corresponding author: Julia Kargl Institute for Experimental and Clinical Pharmacology Medical University of Graz 8010 Graz, Austria -
Anti-Melanoma Activity of AM251
AM251 induces apoptosis and G2/M cell cycle arrest in A375 human melanoma cells Running head: Anti-melanoma activity of AM251 Sara Carpia, Stefano Foglia, Antonella Romaninib, Mario Pellegrinoc, Barbara Adinolfia, Adriano d a a a a Podestà , Barbara Costa , Eleonora Da Pozzo , Claudia Martini , Maria Cristina Breschi , Paola Nieria aDepartment of Pharmacy, University of Pisa, Pisa, Italy; bUniversity Hospital of Pisa, Pisa, Italy; cDepartment of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; dDepartment of Veterinary Sciences, University of Pisa, Pisa, Italy Conflicts of interest The authors declare no conflict of interests. Funding This work was supported by Association against Melanoma Onlus (Italy). Corresponding author: Sara Carpi Department of Pharmacy University of Pisa Via Bonanno 6, 56126 PISA Tel: +39-050-2219539 Fax.: +39-050-2219609 e-mail: [email protected] 1 Abstract Objective. Human cutaneous melanoma is an aggressive and chemotherapy resistant type of cancer. AM251 is a cannabinoid type 1 (CB1) receptor antagonist/inverse agonist with off-target antitumor activity against pancreatic and colon cancer cells. The current study is aimed at characterizing the in vitro anti-melanoma activity of AM251. Methods. The BRAF V600E mutant melanoma cell line, A375, was used as an in vitro model system. Characterization tools included cell viability assay, nuclear morphology assessment, gene expression, western blot, flow cytometry with annexin V-FITC/ 7-AAD double staining, cell cycle analyses, measurements of changes in intracellular cAMP and calcium concentrations. Results. AM251 exerted a remarkable cytotoxic effect against A375 human melanoma cells with potency comparable to that observed for cisplatin without significant changes on the human dermal fibroblasts viability.