Cannabinoids Prevent Emesis Produced by the Cannabinoid CB1 Receptor Antagonist/ Inverse Agonist SR 141716A Nissar A

Total Page:16

File Type:pdf, Size:1020Kb

Cannabinoids Prevent Emesis Produced by the Cannabinoid CB1 Receptor Antagonist/ Inverse Agonist SR 141716A Nissar A BRIEF REPORT ⌬9-Tetrahydrocannabinol and Synthetic Cannabinoids Prevent Emesis Produced by the Cannabinoid CB1 Receptor Antagonist/ Inverse Agonist SR 141716A Nissar A. Darmani, Ph.D. There is substantial clinical evidence that produce emesis via either route of administration. SR ⌬9-tetrahydrocannabinol (⌬9-THC) and its synthetic 141716A at an IP dose of 20 mg/kg was used to induce analogs (nabilone and levonantradol) can prevent emesis in emesis for drug interaction studies. Thus, varying doses of cancer patients receiving chemotherapy. Limited available three different classes of cannabinoid agonists [CP 55, 940 animal studies also support the antiemetic potential of these (0, 0.1, 0.5 and 1 mg/kg), WIN 55, 212-2 (0, 1, 5 and 10 cannabinoids. The present study investigates the mg/kg), and ⌬9-THC (0, 5, 10 and 20 mg/kg)], were mechanism of antiemetic action of cannabinoids in an administered IP to different groups of shrews 10 min prior established animal model of emesis, the least shew to SR 141716A injection. The frequency of emesis was (Cryptotis parva). Since cannabinoid agonists prevent recorded for 30 min following the administration of SR emesis, it was hypothesized that blockade of either the 141716A. The order of potency for redcing both the cannabinoid CB1 receptor or the cannabinoid CB2 receptor frequency of emesis and the percentage of shrews vomiting would induce vomiting. Thus, the emetic potential of SR was CP 55, 940 Ͼ WIN 55, 212-2 Ͼ ⌬9-THC which is 141716A (CB1 receptor antagonist) or SR 144528 (CB2 consistent with an action on the CB1 receptor. These results receptor antagonist) was investigated. Both intraperitoneal suggest that the antiemetic activity of ⌬9-THC and its (0, 1, 2.5, 5, 10 and 20 mg/kg, n ϭ 7–15 per group) and synthetic analogs reside in their ability to stimulate the ϭ subcutaneous (0, 10, 20 and 40 mg/kg, n 6–9 per group) cannabinoid CB1 receptor. Furthermore, the antiemetic ϭ ⌬9 administration of SR 141716A caused emesis (ED50 5.52 potency of CP 55, 940 is 45 times greater than -THC. On Ϯ Ϯ 1.23 and 20.2 1.02 mg/kg, respectively) in the least the other hand, blockade of CB1 receptors can induce shrew in a dose-dependent manner. Indeed, both the vomiting, which implicates an important role for endogenous frequency of emesis and the percentage of animals vomiting cannabinoids in emetic circuits. increased with increasing doses of SR 141716A. Significant [Neuropsychopharmacology 24:198–203, 2001] effects were seen at the 10- and 20-mg/kg doses for the IP © 2000 American College of Neuropsychopharmacology. route, while only the 40-mg/kg dose produced significant Published by Elsevier Science Inc. emesis via the SC route. The CB2 antagonist failed to West Jefferson Street, Kirksville, MO 63501, USA. Tel.: (660) 626- From the Department of Pharmacology, Kirksville College of 2326; Fax: (660) 626-2728. Osteopathic Medicine, Kirksville, Missouri, USA E-mail address: [email protected] Address correspondence to: Dr. Nissar A. Darmani, Department Received April 17, 2000; revised July 14, 2000; accepted August of Pharmacology, Kirksville College of Osteopathic Medicine, 800 21, 2000. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 2 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00197-4 NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 2 Cannabinoid CB1/Receptor and Emesis 199 KEY WORDS: Marijuana; Delta-9-tetrahydrocannabinol; CP volvement of CB1 receptor appears most likely since 55, 940; WIN 55, 212-2; SR 141716A; SR 144528; Emesis; ⌬9-THC produces most of its effects via this site (Pertwee CB1 receptor; CB2 receptor 1997). If activation of cannabinoid receptors prevent eme- In the early 1970s, accumulating anecdotal reports by sis, then blockade of these receptors may produce vomit- young cancer patients suggested that smoking mari- ing. Thus, the present study investigated: (1) whether ad- juana would alleviate the nausea and vomiting caused ministration of the selective cannabinoid CB1-receptor by chemotherapeutic agents. Since then, both govern- antagonist SR 141716A (Rinaldi-Carmona et al. 1994), or ment- and industry-sponsored clinical trials were initi- the CB2-receptor antagonist SR 144528 (Rinaldi-Carmona ated to test the antiemetic potential of ⌬9-tetrahydro- et al. 1998), can induce emesis in the least shrew (Dar- cannabinol (⌬9-THC) and some of its synthetic analogs mani 1998; Darmani et al. 1999); and (2) whether the in- such as nabilone and levonantradol (Gralla 1999; Voth duced emesis can be blocked by the cannabinoid agonists ⌬9 and Schwartz 1997). This literature suggests that both -THC and its newly introduced synthetic analogs CP ⌬9-THC and its tested analogs are useful antiemetics in 55, 940 and WIN 55, 212-2 (Pertwee 1997). some patients for the prevention of nausea and vomit- ing associated with cancer chemotherapy. Though can- nabinoids appear to be a more efficacious class of anti- MATERIALS AND METHODS emetics than dopamine D2 receptor antagonists for the Animals and Drugs prevention of chemotherapy-induced vomiting, the ef- ficacy of tested cannabinoids to date seems not to be as Shrews (Cryptotis parva) were bred and maintained in the high as the more potent antiemetics such as the selec- animal facilities of the Kirksville College of Osteopathic Medicine, Kirksville, Missouri. Both male and female tive 5-HT3 receptor antagonists (Gralla 1999). However, one interesting advantage of cannabinoids is that many shrews (4–6 g, 45–70 days old) were used throughout of the patients who are protected from the acute phase the study. The animals were kept on a 14:10-h light- of emesis, also respond well during the delayed phase dark cycle at a humidity controlled room temperature of 21 Ϯ 1ЊC with ad lib supply of food and water. The of chemotherapy-induced emesis which 5-HT3 receptor antagonists poorly control (Abrahamov et al. 1995; feeding and maintenance of shrews are fully described Chan et al. 1987; Dalzell et al. 1986). elsewhere (Darmani 1998; Darmani et al. 1999). The fol- Unlike the relatively large body of clinical reports, lowing drugs were purchased from Research Biochemi- ⌬9 ⌬9 only a few published animal studies on the antiemetic cals Inc., Natick, MA: -tetrahydrocannabinol ( - ϩ effects of cannabinoids are available. Several cannab- THC) and R( )-WIN 55, 212-2 mesylate. CP 55, 940 was inoids can block cisplatin- or apomorphine-induced obtained from Pfizer (Groton, CT). SR 141716A and SR emesis in a variety of animal species including the cat, 144528 were generously donated by Professor B.R. Mar- the pigeon and the least shrew (Cryptotis parva) (Mc- tin. All drugs were dissolved in a 1:1:18 solution of eth- Carthy and Borison 1981; McCarthy et al. 1984; London anol: emulphor: 0.9% saline to twice the stated drug et al. 1979; Stark 1982; Darmani 2000). Until recently, an concentrations. These drugs concentrations were fur- animal model of emesis had not been employed for in- ther diluted by the addition of an equal volume of sa- vestigating the cannabinoid receptor involved in the line. This procedure was necessary, because the 1:1:18 antiemetic effect of ⌬9-THC and other cannabinoids. In vehicle mixture can cause emesis in up to 20% of ani- the present study, the least shrew (Cryptotis parva) has mals by itself. The final vehicle mixture induced emesis been used as an animal model of emesis. This species only very rarely. All drugs were administered at a vol- was recently introduced as a new serotonergic (Dar- ume of 0.1 ml/10g of body weight. All animals received mani 1998) and dopaminergic (Darmani et al. 1999) ex- care according to the “Guide for the Care and Use of perimental model of vomiting. The least shrew is a Laboratory Animals,” DHSS Publication, revised, 1985. small insectivore (adult weight 4–6 g) that lives in vari- ous ecological niches in Central and North America. Experimental Protocols The family Soricidae, to which shrews belong, consti- tute over 266 species (Churchfield 1990). Over the last The present protocols were based upon our previous decade, Japanese investigators have established the emesis studies in the least shrew (Darmani 1998; Dar- house musk shrew (Suncus murinus) as an experimen- mani et al. 1999). On the test day, the shrews were tal model for the various emetic stimuli (Matsuki et al. transferred to the experimental room and were allowed 1988; Torii et al. 1991). Suncus murinus is relatively a to acclimate for at least 1 h prior to experimentation. larger animal (adult being 50–100 g in weight) and is To habituate the shrews to the test environment, each endogenous to Asia and Africa. animal was randomly selected and transferred to a 20 ϫ While the antiemetic effects of ⌬9-THC appear to be 18 ϫ 21 cm clean clear plastic cage and offered 4 meal receptor-mediated, it is unclear whether the cannabinoid worms (Tenebrio sp) 30 min prior to experimentation. CB1 and/or CB2 receptors are involved in emesis. In- Different groups of shrews were then injected either in- 200 N.A. Darmani NEUROPSYCHOPHARMACOLOGY 2001–VOL. 24, NO. 2 traperitoneally or subcutaneously with vehicle (n ϭ 11– Statistical Analysis 12) or varying doses of the CB antagonist SR 141716A 1 The data were analyzed by the Kruskal-Wallis nonpara- (1, 2.5, 5, 10 and 20 mg/kg, n ϭ 7–15), or the CB antag- 2 metric one-way analysis of variance (ANOVA) and onist SR 144528 (10, 20 and 40 mg/kg, n ϭ 8–11 per posthoc analysis by Dunn’s multiple comparisons test. group). Immediately following injection, each shrew A p-value of Ͻ.05 was necessary to achieve statistical was placed in the observation cage and the onset la- significance.
Recommended publications
  • Chapter Four – TRPA1 Channels: Chemical and Temperature Sensitivity
    CHAPTER FOUR TRPA1 Channels: Chemical and Temperature Sensitivity Willem J. Laursen1,2, Sviatoslav N. Bagriantsev1,* and Elena O. Gracheva1,2,* 1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA 2Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA *Corresponding author: E-mail: [email protected], [email protected] Contents 1. Introduction 90 2. Activation and Regulation of TRPA1 by Chemical Compounds 91 2.1 Chemical activation of TRPA1 by covalent modification 91 2.2 Noncovalent activation of TRPA1 97 2.3 Receptor-operated activation of TRPA1 99 3. Temperature Sensitivity of TRPA1 101 3.1 TRPA1 in mammals 101 3.2 TRPA1 in insects and worms 103 3.3 TRPA1 in fish, birds, reptiles, and amphibians 103 3.4 TRPA1: Molecular mechanism of temperature sensitivity 104 Acknowledgments 107 References 107 Abstract Transient receptor potential ankyrin 1 (TRPA1) is a polymodal excitatory ion channel found in sensory neurons of different organisms, ranging from worms to humans. Since its discovery as an uncharacterized transmembrane protein in human fibroblasts, TRPA1 has become one of the most intensively studied ion channels. Its function has been linked to regulation of heat and cold perception, mechanosensitivity, hearing, inflam- mation, pain, circadian rhythms, chemoreception, and other processes. Some of these proposed functions remain controversial, while others have gathered considerable experimental support. A truly polymodal ion channel, TRPA1 is activated by various stimuli, including electrophilic chemicals, oxygen, temperature, and mechanical force, yet the molecular mechanism of TRPA1 gating remains obscure. In this review, we discuss recent advances in the understanding of TRPA1 physiology, pharmacology, and molecular function.
    [Show full text]
  • Cannabinoid Receptor and Inflammation
    Cannabinoid Receptor and Inflammation Newman Osafo1, Oduro Yeboah1, Aaron Antwi1, and George Ainooson1 1Kwame Nkrumah University of Science and Technology September 11, 2020 Abstract The eventual discovery of endogenous cannabinoid receptors CB1 and CB2 and their endogenous ligands has generated interest with regards to finally understanding the endocannabinoid system. Its role in the normal physiology of the body and its implication in pathological states such as cardiovascular diseases, neoplasm, depression and pain have been subjects of scientific interest. In this review the authors focus on the endogenous cannabinoid pathway, the critical role of cannabinoid receptors in signaling and mediation of neurodegeneration and other inflammatory responses as well as its potential as a drug target in the amelioration of some inflammatory conditions. Though the exact role of the endocannabinoid system is not fully understood, the evidence found leans heavily towards a great potential in exploiting both its central and peripheral pathways in disease management. Cannabinoid therapy has already shown great promise in several preclinical and clinical trials. 1.0 Introduction Ethnopharmacological studies have shown the use of Cannabis sativa in traditional medicine for over a thousand years, with its widespread use promoted by its psychotropic effects (McCoy, 2016; Turcotte et al., 2016). The discovery of a receptor within human body, that is selectively activated by cannabinoids suggested the presence of at least one endogenous ligand for this receptor. This is confirmed by the discovery of two endogenously synthesized lipid mediators, 2-arachidonoyl-glycerol and arachidonoylethanolamide, which function as high-affinity ligands for a subfamily of cannabinoid receptors ubiquitously distributed in the central nervous system, known as the CB1 receptors (Turcotte et al., 2016).
    [Show full text]
  • Nabilone for Chronic Pain Management: a Review of Clinical Effectiveness, Safety, and Guidelines
    TITLE: Nabilone for Chronic Pain Management: A Review of Clinical Effectiveness, Safety, and Guidelines DATE: 11 November 2011 CONTEXT AND POLICY ISSUES Cannabis sativa is a flowering plant that has long been used as a recreational drug, and for medicinal purposes.1,2 The main psychoactive component of cannabis is delta-9- tetrahydrocannabinol (∆9-THC).2 Nabilone (Cesamet®) is an oral synthetic cannabinoid, which is licensed in Canada for treating patients with severe nausea and vomiting related to chemotherapy for cancer and who have failed to respond adequately to conventional antiemetic treatments.2-4 Clinical trials and anecdotal reports have suggested that the use of nabilone in other medical conditions, such as appetite stimulation, anxiety, spasticity, and pain.1,5 Chronic pain affects approximately one in five people in developed countries and two in five in less well-resourced countries. In many circumstances, the patient’s quality of life is poor due to persistent pain caused either by an ongoing illness or nerve damage caused by the disease after resolution or cure of the disease.6 Multiple sclerosis (MS) is a neurodegenerative disease, and is the most common cause of neurological disability in young people, with an average age of onset around 30 years and a prevalence of about 120 per 100,000 individuals in North America. The majority of patients with MS display symptoms, such as fatigue, muscle stiffness or spasticity, pain, memory problems, balance trouble, tremors, urinary disturbance, and sexual dysfunctions.2,7 The purpose of this review is to assess the evidence of benefits and harms related to the use of nabilone in management of chronic pain, including patients with MS.
    [Show full text]
  • N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation Via Nonhematopoietic TRPV1
    N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1 This information is current as Samira K. Lawton, Fengyun Xu, Alphonso Tran, Erika of October 1, 2021. Wong, Arun Prakash, Mark Schumacher, Judith Hellman and Kevin Wilhelmsen J Immunol 2017; 199:1465-1475; Prepublished online 12 July 2017; doi: 10.4049/jimmunol.1602151 http://www.jimmunol.org/content/199/4/1465 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/07/12/jimmunol.160215 Material 1.DCSupplemental http://www.jimmunol.org/ References This article cites 69 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/199/4/1465.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1 Samira K.
    [Show full text]
  • NIDA's Drug Facts on Synthetic Cannabinoids (K2/Spice)
    Synthetic Cannabinoids (K2/Spice) Revised February 2018 What are synthetic cannabinoids? Synthetic cannabinoids are human-made mind-altering chemicals that are either sprayed on dried, shredded plant material so they can be smoked or sold as liquids to be vaporized and inhaled in e-cigarettes and other devices. These products are also known as herbal or liquid incense. These chemicals are called cannabinoids because they are similar to chemicals found in the marijuana plant. Because of this similarity, synthetic cannabinoids are sometimes misleadingly called "synthetic marijuana" (or "fake weed"), and they are often marketed as safe, legal alternatives to that drug. In fact, they are not safe and may affect the brain much more powerfully than marijuana; their actual effects can be unpredictable and, in some cases, more dangerous or even life-threatening. Synthetic cannabinoids are part of a group of drugs called new psychoactive substances (NPS). NPS are unregulated mind-altering substances that have become newly available on the market and are intended to produce the same effects as illegal drugs. Some of these substances may have been around for years but have reentered the market in altered chemical forms, or due to renewed popularity. False Advertising Synthetic cannabinoid products are often labeled "not for human consumption." Labels also often claim that they contain "natural" material taken from a variety of plants. However, the only parts of these products that are natural are the dried plant materials. Chemical tests show that the active, mind-altering ingredients are cannabinoid compounds made in laboratories. Synthetic Cannabinoids • February 2018 • Page 1 Manufacturers sell these products in colorful foil packages and plastic bottles to attract consumers.
    [Show full text]
  • Pharmacology for PAIN: Prescribing Controlled Substances
    The Impact of Pain Pharmacology for PAIN: The National Center for Health Prescribing Controlled Statistics estimates that 32.8% of the U.S. population has persistent pain ~94 million U.S. residents have episodic or Substances persistent pain (1 in every 5 adults) Judith A. Kaufmann, Dr PH, FNP-BC Treatment for chronic pain rarely Robert Morris University results in complete relief and full functional recovery Of patients diagnosed with chronic pain and treated by a PCP, 64 percent report persistent pain two years after treatment initiation US Statistics: The Alarming Impact of Pain Facts Pain ranks low on medical tx priority Americans constitute 4.6% of world’s only 15% of primary care physicians report that they "enjoy" treating patients with chronic pain population-but consume ~ 80% of world’s Dahl et al., and Redford (2002) found that patients opioid supply said they fear dying in pain more than they fear death Americans consume 99% of world supply of hydrocodone Pain over the past 10 years has been designated the 5th vital sign Between 1999 and 2006, the number of people >age 12 using illicit prescription Pain is 3rd leading cause of absence pain relievers doubled from 2.6 to 5.2 from work million 2006 National Survey on Drug Use and Health (NSDUH) Are we the Pushers? Can we be found guilty? Since 1999, opioid analgesic poisonings on 55.7% of users obtained drugs from a death certificates increased 91% friend or relative who had been prescribed the drugs from 1 provider During same period, fatal heroin and cocaine poisonings increased 12.4% and 22.8% 19.1% of users obtained their drug directly respectively from 1 provider In 2008, 36,450 opioid deaths were 1.6% reported doctor shopping reported 3.9% reported purchasing drugs from a CDC, 2011 dealer Male:female ratio = 1.5:1 but death rate for females ia 20x higher than males 1 Is opioid abuse a recent Classifications of Pain phenomenon? Acute V.
    [Show full text]
  • Frequently Asked Questions About Synthetic Drugs
    FREQUENTLY ASKED QUESTIONS ABOUT SYNTHETIC DRUGS WHAT ARE SYNTHETIC DRUGS? WHAT DOES THE PACKAGING OF SYNTHETIC CANNABINOIDS LOOK LIKE? A SYNTHETIC DRUG, ALSO REFERRED TO AS A Many of the products are sold in colorful packets with names DESIGNER DRUG, IS A CHEMICAL INTENDED TO that appeal to adolescents and young adults. Manufacturers IMITATE THE PROPERTIES AND EFFECTS OF A label the packages as “not for human consumption” and KNOWN HALLUCINOGEN OR NARCOTIC AND market the products as incense or potpourri to mask the MAY HAVE UNKNOWN SIDE EFFECTS OR CAUSE intended purpose and to avoid regulatory oversight of AN ADVERSE REACTION. THESE DRUGS ARE the manufacturing process. You can view examples of the packaging on page 3. CREATED IN ORDER TO EVADE RESTRICTIONS AGAINST ILLEGAL SUBSTANCES. ARE SYNTHETIC CANNABINOIDS ARE SYNTHETIC DRUGS LEGAL IN TEXAS? DANGEROUS? No. Under state law, it is a crime to manufacture, deliver or Synthetic cannabinoids possess a synthetic drug. are illegal, dangerous, highly addictive and WHAT ARE SYNTHETIC CANNABINOIDS? potentially deadly. One Synthetic cannabinoids are commonly referred to as K2, of the original chemists Kush, Spice, synthetic marijuana and fake weed. They are who designed synthetic a mix of plant matter sprayed with chemicals in sometimes cannabis for research purposes, John Huffman, Ph.D., likened dangerously high proportions, falsely marketed as “legal recreational use of synthetic drugs to playing Russian highs” and smoked like marijuana. roulette. The contents and effects of synthetic cannabinoids WHERE ARE SYNTHETIC CANNABINOIDS SOLD? are unpredictable due to a constantly changing variety of Synthetic cannabinoids are relatively inexpensive and sold chemicals used in manufacturing processes devoid of quality in convenience stores, smoke shops, novelty stores, on the controls and government regulatory oversight.
    [Show full text]
  • Cannabis, the Endocannabinoid System and Immunity—The Journey from the Bedside to the Bench and Back
    International Journal of Molecular Sciences Review Cannabis, the Endocannabinoid System and Immunity—The Journey from the Bedside to the Bench and Back Osnat Almogi-Hazan * and Reuven Or Laboratory of Immunotherapy and Bone Marrow Transplantation, Hadassah Medical Center, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel; [email protected] * Correspondence: [email protected] Received: 21 May 2020; Accepted: 19 June 2020; Published: 23 June 2020 Abstract: The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.
    [Show full text]
  • Medicinal Chemistry Endeavors Around the Phytocannabinoids
    CHEMISTRY & BIODIVERSITY – Vol. 4 (2007) 1707 REVIEW Medicinal Chemistry Endeavors around the Phytocannabinoids by Eric Stern and Didier M. Lambert* Drug Design and Discovery Center and Unite´ de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculte´ de Me´decine, Universite´ catholique de Louvain, Avenue E. Mounier 73, U.C.L. 73.40, B-1200 Bruxelles (phone: þ3227647347; fax: þ3227647363; e-mail: [email protected]) Over the past 50 years, a considerable research in medicinal chemistry has been carried out around the natural constituents of Cannabis sativa L. Following the identification of D9-tetrahydrocannabinol (D9-THC) in 1964, critical chemical modifications, e.g., variation of the side chain at C(3) and the opening of the tricyclic scaffold, have led to the characterization of potent and cannabinoid receptor subtype-selective ligands. Those ligands that demonstrate high affinity for the cannabinoid receptors and good biological efficacy are still used as powerful pharmacological tools. This review summarizes past as well as recent developments in the structure–activity relationships of phytocannabinoids. 1. Introduction. – Despite the wide uses of preparations of the hemp Cannabis sativa L. during the History, the modern pharmacology of natural cannabinoids has been hampered by the slow progress in the elucidations of the chemical structures of its major components. Indeed, it is nowadays known that more than 70 compounds derived from a diterpene structure are present in the plant [1], and this fact may explain the difficulty to obtain pure chemical entities in the past. In addition, the medicinal research for more than a half century has been driven by the search for the components responsible for the psychoactive effects of cannabis, this era in the history of the chemical research on cannabinoids have been recently reviewed [2][3].
    [Show full text]
  • Article 22 Regulation for Restriction of Synthetic Drugs
    ARTICLE 22 REGULATION FOR RESTRICTION OF SYNTHETIC DRUGS SECTION 22.1 AUTHORITY This regulation is promulgated under the authority granted to the Needham Board of Health under Massachusetts General Laws Chapter 111, Section 31 which states that “boards of health may make reasonable health regulations”. SECTION 22.2 PURPOSE The Needham Board of Health has found that synthetic marijuana, consisting of plant or other material treated with various chemicals or other synthetic substances not approved for human consumption, may be marketed and sold as herbal incense in the greater Boston area, although they are being used in the same manner and for the same purposes as scheduled drugs. In addition, the use of these products has become particularly popular among teens and young adults. Based on information and reports from hospitals, emergency room doctors, and police agencies, individuals who use these products experience dangerous side effects including convulsions, hallucinations, and dangerously elevated heart rates. This is evidence that synthetic marijuana products are harmful if inhaled or consumed, and present a significant public health danger. These synthetic compounds and others have a high potential for abuse and lack of any accepted medical use, these dangerous products, while not approved for human consumption, are marketed and sold in a form that allows for such consumption, putting at risk the individuals who come into contact with them. Therefore, the Needham Board of Health adopts this regulation for the purpose and with the intent to protect the public health and safety of the Town of Needham and its residents from the threat posed by the availability and use of synthetic marijuana, synthetic stimulants, synthetic hallucinogens, and other dangerous products by prohibiting persons from trafficking in, possessing, and using them within the town.
    [Show full text]
  • Federal Register/Vol. 84, No. 214/Tuesday, November 5, 2019
    Federal Register / Vol. 84, No. 214 / Tuesday, November 5, 2019 / Notices 59645 Authority: 42 U.S.C. 6213; and 30 CFR company plans to bulk manufacture Controlled substance Drug Schedule 556.511–556.515. these drugs as synthetics. No other code Walter D. Cruickshank, activities for these drug codes are Hydromorphone ....................... 9150 II Acting Director, Bureau of Ocean Energy authorized for this registration. Hydrocodone ............................ 9193 II Management. Morphine .................................. 9300 II Dated: October 18, 2019. Oripavine .................................. 9330 II [FR Doc. 2019–24052 Filed 11–4–19; 8:45 am] William T. McDermott, Thebaine .................................. 9333 II BILLING CODE 4310–MR–P Assistant Administrator. Opium extracts ......................... 9610 II Opium fluid extract ................... 9620 II [FR Doc. 2019–24107 Filed 11–4–19; 8:45 am] Opium tincture ......................... 9630 II BILLING CODE 4410–09–P Opium, powdered .................... 9639 II DEPARTMENT OF JUSTICE Opium, granulated ................... 9640 II Oxymorphone .......................... 9652 II Drug Enforcement Administration Noroxymorphone ..................... 9668 II DEPARTMENT OF JUSTICE Tapentadol ............................... 9780 II [Docket No. DEA–536] Drug Enforcement Administration The company plans to manufacture Bulk Manufacturer of Controlled [Docket No. DEA–526] the listed controlled substances as an Substances Application: Organix, Inc. Active Pharmaceutical Ingredient (API) Bulk
    [Show full text]
  • Synthetic Cannabis
    Global emergence of synthetic cannabinoids Source: https://www.unodc.org/LSS/SubstanceGroup/Details/ae45ce06-6d33-4f5f-916a- e873f07bde02 Source: UNODC questionnaire on NPS, 2012 Background The appearance of ‘herbal highs’ in the market is not a new phenomenon. Such products usually consisted of plant mixtures with little psychoactive effects. Since 2004, however, the composition of these herbal products seems to have substantially changed to include potent new psychoactive compounds known as synthetic cannabinoids. Research on the mechanism of cannabis activity dates back several decades when molecules with similar behaviour to Δ9-tetrahydrocannabinol (THC) were first examined. A synthetic analogue of THC , ‘HU-210’, was first synthesized in Israel in 1988[1]and is considered to have a potency of at least 100 times more than THC. Due to its similar chemical structure to THC, ‘HU-210’ is regarded as a ‘classical cannabinoid’ and has been found in synthetic cannabinoids sold in the United States and other countries. Non-classical cannabinoids include cyclohexylphenols or 3-arylcyclohexanols (‘CP’compounds). ‘CP’ compounds were developed as potential analgesics by a pharmaceutical company in the 1980s. Respondents to the UNODC questionnaire on NPS have reported the emergence of CP-47,497 and CP-47,497-C8 in numerous countries in all regions except Africa since 2009. Other structurally dissimilar varieties of synthetic cannabinoids unrelated to THC have also emerged on the market. These include aminoalkylindoles, such as naphthoylindoles (e.g. JWH-018), phenylacetylindoles (e.g. JWH-250), and benzoylindoles (e.g. AM-2233).[2] JWH-018, arguably the most widely known synthetic cannabinoid, belongs to the group of aminoalkylindoles and is considered to be three times as potent as THC.
    [Show full text]