DOCSLIB.ORG

( 12 ) United States Patent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
( 12 ) United States Patent US009855225B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 ,855 ,225 B2 Eisenstein et al. ( 45) Date of Patent : Jan . 2 , 2018 I ( 54 ) CANNABINOID RECEPTOR TREATMENTS A61K 31/ 404 (2006 .01 ) A61K 31 /415 (2006 .01 ) ( 75 ) Inventors : Toby K . Eisenstein , Wyndmoor, PA A61K 31/ 454 ( 2006 . 01 ) (US ) ; Rebecca R . Hartzell , Indian A61K 39 / 395 ( 2006 .01 ) Rocks Beach , FL (US ) ; Martin W . A61K 45 /06 ( 2006 .01 ) Alder , Warrington , PA (US ) ; Joseph J . COZK 16 / 24 ( 2006 .01 ) Meissier, Ardmore , PA (US ) (52 ) U . S . Cl. ( 73 ) Assignee : TEMPLE UNIVERSITY OFFICE OF CPC . .. A61K 31 /09 (2013 . 01 ) ; A61K 31/ 095 TECHNOLOGY TRANSFER , ( 2013 .01 ) ; A61K 31 /35 (2013 . 01 ) ; A61K Philadelphia , PA (US ) 31 /352 ( 2013 .01 ) ; A61K 31 /404 ( 2013 .01 ) ; A61K 31/ 415 ( 2013 . 01 ) ; A61K 31/ 454 ( * ) Notice : Subject to any disclaimer, the term of this ( 2013 . 01 ) ; A61K 39 /3955 ( 2013 .01 ) ; A61K patent is extended or adjusted under 35 45 /06 ( 2013. 01 ) ; CO7K 16 /244 ( 2013 .01 ) U . S . C . 154 ( b ) by 101 days . (58 ) Field of Classification Search CPC .. .. .. .. .. A61K 31 /09 ; A61K 31/ 095 (21 ) Appl. No. : 14 /239 , 413 See application file for complete search history. (22 ) PCT Filed : Aug. 17 , 2012 (56 ) References Cited ( 86 ) PCT No. : PCT/ US2012 / 051330 U . S . PATENT DOCUMENTS $ 371 (c ) ( 1 ) , 2005/ 0159449 Al * 7 / 2005 Martin .. .. CO7D 303 / 10 ( 2 ) , ( 4 ) Date : Feb . 26 , 2016 514 /317 2008/ 0139635 A1* 6 / 2008 Martin .. .. A61K 31 /045 (87 ) PCT Pub. No. : W02013 /025984 514 / 397 PCT Pub . Date : Feb . 21, 2013 * cited by examiner (65 ) Prior Publication Data Primary Examiner — Yong Chong US 2017 /0014355 A1 Jan . 19 , 2017 ( 74) Attorney , Agent, or Firm — Duane Morris LLP Related U . S . Application Data (57 ) ABSTRACT (60 ) Provisional application No . 61/ 524 , 883, filed on Aug. The present invention includes methods and compositions 18 , 2011 . for treating a transplant recipient by administration of a CB2 receptor agonist either alone or in combination with one or (51 ) Int . Ci. more active pharmaceutical ingredients to block the rejec A61K 31 / 09 ( 2006 . 01 ) tion of foreign tissue and prolong grafted organs, tissues and A61K 31/ 095 ( 2006 .01 ) cells . A61K 31/ 35 ( 2006 .01 ) A61K 31 / 352 ( 2006 .01 ) 6 Claims, 16 Drawing Sheets U . S . Patent Jan . 2 , 2018 Sheet 1 of 16 US 9 ,855 , 225 B2 FIGURE 1A FIGURE 1B 14W Work Ooooo ! USU * * *HANS . SYNET W* with SuppressionIndex#SD ** - Artikel in SuppressionIndexSD Unawe engooszt nem tuumarket Wwwwwwwwwwwwwww ... - 4 .tami** reiman w i sh wwwy Concentration 0 - 1966 (UM ) Concentrati JWH - C . mytom JWH -015 1444 0 . 1966 (CB , antagonist) (C8 , antagonist) Ethanol Vehicle { 0 . 5 % 3 .2 x 10 + M m . 3 . 2 * 10 - $ _ M & Eth??? ??ce in 1 .6 x 10 - 1 , 6 x 10M 6 . 4 x 10 M 6 , 4 x 10 -5M NNmet n 32 X 10 .5M . .. 3 .2x10 -SM U . S . Patent Jan . 2 , 2018. Sheet. 2 of 16 . US 9 ,855 , 225 B2 No treatment ????? R ocou RAWANNATA Y * * * * WWWWWWWWWWWWWScatters SES 250 YYYY 250 * * WOWWWWWWWWWWW W W (000*1) (1,000) 200 200 H 150 KKKKKKKKKKKKKKKKKKKKXXWWWYX AKAAMAAN 150 LIVE Dead Live Dead VOS: wwws V FSC valentineverlopenminderbareenveranstidostermeWWW LLVATTEN 100instalimbaliistenilendeshalbenhandbookinterestingochwypotherthan 100 hAwwwwwA * * * * * * * * * * * * 50 xwwwww 50 AMMA L VARAVWAWALAWWARRAK KARSHA Aishah 102 10 % 10 % 10 % TRAXXX Up VioletPacific Blue UD Violet Pacific Blue VYYYYYE VYUWUWUWMWWWWMWWWWMWWURMENANNA VANAVUW VWvWULYVUMILVUKAVVA WAVUVUN LWLAXY wanawanawa UVUDUNYASTERCRAFTER W . W . 444 .4V 44AAAAAA WWWWWWWWWWWWWWWWWWWWWWWWwwwwwwwwwwwNWANAWAWAWAKANAN Figure 2 . U . S . Patent Jan . 2 , 2018 Sheet 3 of 16 US 9 ,855 , 225 B2 FIGURE 3A W wwwwwwwwwwwwwwwwwwwwwwwwwwwww w w w wwwwww No treatment * * * * * * maging WT: EthanolVehicle betpotestanti *TA KA KO : JWH -015 USDIndexSuppression s me KO : Ethanol Vehicle .cat wwwwwwwwwwwwwwww CLUTC wat er in WT: JWH -015 D0 .. 0m W to LURILEOSLOBODAWWW20 . 22- 921 cen JWH * Wa* * inwwwwwwwwwwwwwwwww ???????. (KKK OCH SOU OD 0 0 op die see imao No Treatment * WWWSAWAW A LA WWW . H 0 . 8 * WT: DMSO Vehicle SDIndex+Suppression KO : DMSO Vehicle The x00000000000000000000000SARURAXX KO : 01966 M A XXX THILDE #3 * WT: 0 -1966 OSW. 10 20 30 40 50 Concentration 0 - 1966 (1M ) FIGURE 3B U . S . Patent Jan . 2 , 2018 Sheet 4 of 16 US 9 ,855 , 225 B2 FIGURE 4A 600 espectadors del EMESES 9 . WORYna wa n aoty XYMAXNo treatment 00 Sexo opaguodoogooooooo w Ethanol Vehicle IL-2(pg/mL) * w JWH -015 w tooteggere 2 4 16 32 Concentration JWH -015 ( M ) 6007PODCOCOCO ogP C * * o hraneifrom ti 400 ) INanomat WT: DMSO Vehicle IL-2(pg/mL) KO : 0 - 1966 * atau * en on KO : DMSO Vehicle * * * * montering WT: 0 - 1966 cococacoooooooooooooooooooooooooooooduonossono be 1 2 4 8 16 32 ConcenConcentration 0 - 1966 ( UM ) FIGURE 4B U . S . Patent Jan . 2 , 2018 Sheet 5 of 16 US 9 ,855 , 225 B2 FIGURE 5A per proposition .com ww com secados aos m . ourMes e n in **im No treatment SDIndexSuppression foreld Ethanol Vehicles fyrir go2207000goodwodowv0000000000000000000000 . .. one CD11b * Cells Treated **** 0 MAAerabic * No Separation ? 2 oppongponsores momento$ constante16 semok 32 KA ook om ' ou moin s or w wo wo wo wo wwwpood No treatment ANGKOLSANSIBUS AURAWANNATA KARUNASLEDKOOPS19 DMSO Vehicles de SuppressionIndexUSD CD11b * Treated * * * lampe CD3* Treated Bon e No Separation XXURY 210X12XN 9 ze Rooooooooooooooooowwwwwww homecomme FIGURE 5B U . S . Patent Jan . 2 , 2018 Sheet 6 of 16 US 9 ,855 , 225 B2 W oooOOOOOO0000000000000000000000000000000000000000000000000000 doods O word.com o FoldChangeONWA ooooooooooooooo OOOOooooo000000000000ooooooooodangandosto sowe Socs5sooooooooo Sla2 L - 10 Cyclin ??????????????????D3 CD40L Figure 6 U . S . Patent Jan . 2 , 2018 Sheet 7 of 16 US 9 ,855 , 225 B2 0 - 1966 * IL-10(pg/ml) * o n . to v . wwwa Wa vo memea with.www wat wes * apiyeA * p < p apun * ** p < 00 . 0101 2 4 8 16 32 Concentration 0 - 1966 (UM ) Figure 7 U . S . Patent Jan . 2 , 2018 Sheet 8 of 16 US 9 ,855 , 225 B2 PercentTregs oba * p < 0 .01 0 24 48 II Time (hours ) No TreatmentTreatme go Vehicle 0 -1966 ($ 32 PM ) Figure 8 U . S . Patent Jan . 2 , 2018 Sheet 9 of 16 US 9 ,855 , 225 B2 ooo0000000000000000 poooooooooooooooooooooooooooooooooooo o oooo o o va Vehicles Exer * * 2 . Y a p , R299 * * * * * * * No Treatment P ASSALAMU WANN A LA ' up ve asXapusuoisselddns * ANN * withNNNNNNN ? XXXX * * A WWW on and . pomarawwwwwwwwwwwwwtocoLALO vetene anti L 10 ( 1 uglmL ) * No antibody O. BA 32 Concentration 0 - 1966 (UM ) Figure 9 U . S . Patent Jan . 2 , 2018 Sheet 10 of 16 US 9 ,855 ,225 B2 PercentTregs WWW Wooowoooo No Vehicle 0 . 1966 Q . 1966 O 1966 Treatment 32 um 16uM 8AM No Antibody 1 . 0 ug mL/ 1 . 6 ugml/ Figure 10 enU . S . Patentmoet wowJan . 2 , 2018 Sheet. 11. of 16 . US 9 ,855 ,225 B2 XX X * * * 4 ???????????10 12 14 Day (Post operative ) gent 0 - 1966 Vehicle Figure 11 0 atent Jan . 2 , 2018 Sheet 12 of 16 US 9 , 855 ,225 B2 000000AAAAAAAA A INCA 0000000000000000A ? MeancPMx103SD woooowwook Sinatia. ? * * 0 . 00 Vehicle 1966 Figure 12 . U . S . Patent Jan . 2 , 2018 Sheet 13 of 16 US 9 ,855 ,225 B2 ooooooo XXXXXXXX000000odds Foxp3*cells(%ofCD4+Cells) oooooooooooooooooooooo0000000oooooooooooooooo SAXXXXXXX qöboooooooooooooo * p < 0 .01 Vehicle 0 . 1966 Figure 13 atent Jan . 2 , 2018 Sheet 14 of 16 US 9 ,855 ,225 B2 1494D DDDDD ws %Tregs 4 WWW 0 . 01 Vehicle 0 - 1966 Figure 14 atent Jan . 2 , 2018 Sheet 15 of 16 US 9 , 855 ,225 B2 8 mmmmmm |_.sowwuxiaomusion Assong * : ?? :??? ?? Seedassales : ???? A & A WATEPHETTERIEF?? w ???? ?? ? ? ? ? ? * p < 0 .07 HYMERCEL P HYTHINHWYNNINTENTREMAINMENTENTANINGO?? - rainternaturernmenternerationarriveryWen S-SG · ProErg Vehicie 0.956 and Prograft Figite 13 U . S . Patent Jan . 2 , 2018 Sheet 16 of 16 US 9 ,855 ,225 B2 www wwwwwwwwWEUSKAS * ** Www w * * alebo mama wa mig * s KOOUOO od SpleenWeightindex(Percent) Www . * * . * * * * * * * * p < 0 .01 $ $ oooooooooowwwwwOROKOKAKKO * p < 0 .05 WeddiwWRBusiness posesi n in new wine anges O-1966 Prograr Vehicle 0-1966 and Prograf Figure 16 US 9 ,855 ,225 B2 CANNABINOID RECEPTOR TREATMENTS results demonstrate that both exogenous and endogenous cannabinoids exert their effect on the immune system CROSS -REFERENCE TO RELATED through CB2 receptors . APPLICATIONS It has been shown that broad spectrum cannabinoid ago 5 nists have potential as therapeutic agents , however, their This application is a U . S . national phase application filed medicinal use may be limited because of use and abuse . For under 35 U . S . C . $ 371 of International Application No .: example , one of the drawbacks of using marijuana , a CB , PCT/ US2012 /051330 , which was filed Aug . 17 , 2012 , and CB2 receptor agonist, is the resulting psychotropic effects which claimsthe benefit of the filing date of U . S . Provisional due to CB2 receptor activation . Cannabinoids that selec Application No . 61 / 524 ,883 , which was filed on Aug . 18 , " tively target CB , receptors , and thus , the immune system , 2011. For the purpose ofany U . S . application that may claim have great clinical potential as therapeutic agents in the the benefit of U . S . Provisional Application No . 61/ 524 , 883 , treatment of graft rejection since they are expected to have the contents of that earlier filed application are hereby little or no CB , receptor activity ( i. e . psychotropic effects ) . incorporated by reference in their entirety . Current immunosuppressant therapies used to prevent or 15 block tissue rejection in organ transplantation are associated U . S . GOVERNMENT RIGHTS with significant untoward effects . For example, toxicity with chronic tacrolimus use is associated with post - transplanta This invention was supported in part by United States tion diabetes mellitus (PTDM ) due to the death of pancreatic Government Grant No . DA13429 , DA06650 and T32 - 20 islet cells , and also with kidney damage . Tacrolimus and DA07237 awarded by National Institutes of Drug Abuse .
Load more

Recommended publications
  • Effects of Cannabinor, a Novel Selective Cannabinoid 2 Receptor Agonist, on Bladder Function in Normal Rats
    EURURO-3374; No. of Pages 8 EUROPEAN UROLOGY XXX (2010) XXX–XXX available at www.sciencedirect.com journal homepage: www.europeanurology.com Voiding Dysfunction Effects of Cannabinor, a Novel Selective Cannabinoid 2 Receptor Agonist, on Bladder Function in Normal Rats Christian Gratzke a,b,f, Tomi Streng c, Christian G. Stief b, Thomas R. Downs d, Iris Alroy e, Jan S. Rosenbaum d, Karl-Erik Andersson f,*, Petter Hedlund a,g a Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden b Department of Urology, Ludwig-Maximilians-University, Munich, Germany c Department of Pharmacology, Turku University, Finland d Women’s Health, Procter & Gamble Health Care, Cincinnati, OH, USA e Pharmos Limited, Rehovot, Israel f Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA g Urological Research Institute, San Raffaele University Hospital, Milan, Italy Article info Abstract Article history: Background: Cannabinoid (CB) receptors may be involved in the control of bladder Accepted February 19, 2010 function; the role of CB receptor subtypes in micturition has not been established. Published online ahead of Objectives: Our aim was to evaluate the effects of cannabinor, a novel CB2 receptor print on March 1, 2010 agonist, on rat bladder function. Design, setting, and participants: Sprague Dawley rats were used. Distribution of Keywords: CB2 receptors in sensory and cholinergic nerves of the detrusor was studied. Cannabinoid Selectivity of cannabinor for human and rat CB receptors was evaluated. Effects Urothelium of cannabinor on rat detrusor and micturition were investigated. Sensory Measurements: Immunohistochemistry, radioligand binding, tritium outflow Detrusor assays, organ bath studies of isolated bladder tissue, and cystometry in awake Cystometry rats were used.
    [Show full text]
  • Introduction
    INTRODUCTION 1 1.1 Cannabis The hemp plant Cannabis sativa L., (Cannabaceae), native to Central Asia (probably north Afghanistan) has been used for medicinal purposes for millenia across many cultures. The first evidence of its therapeutic properties dates back to a description of the drug in a Chinese compendium of medicines at the time of the Chinese emperor Shen Nung dated 2737 B.C. In the 19th century the drugs were widely prescribed in the Western world for the treatment of cough, fatigue, rheumatism, asthma, delirium tremens, migraine headache, constipation and dysmenorrhea (Grinspoon, 1969). In addition to its great therapeutic potential, cannabis is known by numerous names such as marijuana, weed, blow, gear, grass and is the most commonly used illicit drugs among recreational substance abusers throughout the world. In many countries statistics quote that more than 50 % of young people have used it at least once (Iversen, 2005). The possession of cannabis was first banned in 1915, in California. Although cannabis became illegal in the USA, it was in the British pharmacopoeia and was occasionally used until 1971 when its use was outlawed in Misuse of Drugs Act (Baker et al., 2003). The most probable reason for the abuse is the action of the main psychoactive component of marijuana, (-)-∆9–tetrahydrocannabinol (∆9–THC), on the central nervous system (CNS), affecting cognition, memory and mood. After long-term cannabis use, mostly at high intake levels there is some evidence about it causing psychosocial harm to the user (lower educational achievement, 2 psychiatric illnesses- schizophrenia, depression, anxiety) but by comparison with other „recreational‟ drugs, cannabis is a relatively safe drug (Iversen, 2005).
    [Show full text]
  • Kannabinoidlerin Farmakolojisi
    KANNABİNOİDLERİN FARMAKOLOJİSİ Prof. Dr. Ahmet ULUGÖL Trakya Üniversitesi Tıp Fakültesi Tıbbi Farmakoloji Anabilim Dalı Kannabis (kenevir) esrar, marijuana, haşiş Kannabinoidler Fitokannabinoidler (doğal kannabinoidler) Sentetik kannabinoidler ve analogları Endokannabinoidler Araşidonil etanolamin (anandamid, AEA) 2-araşidonilgliserol (2-AG), vb. Fitokannabinoidler Δ9-tetrahidrokannabinol (THC) (psikoaktif) Kannabidiol (CB reseptörlere afinite, psikoaktif değil) Kannabinol Δ9-tetrahidrokannabivarin Δ9-tetrahidrokannabiorkol Kannabigerol Kannabikromen, vb. Sentetik kannabinoidler ve analogları Dronabinol (sentetik THC, Marinol) Nabilon (dronabinol analogu, Cesamet) THC + kannabidiol (Nabiximols, Sativex) Levonantradol, metanandamid WIN 55,212-2, HU-210, CP 55,940 CT-3 (ajulemik asit) rimonabant (SR141716A, Acomplia), vb. Endokannabinoidler Endokannabinoi CB1 CB2 TRPV1 d Anandamid +++ + + 2-AG +++ ++ 0 Virodhamin Agonist/parsiyel + 0 agonist N-araşidonil-dopamin +++ 0 +++ Noladin ether +++ + 0 CB1 & CB2 reseptörlerinin dağılımı CB1 CB2 immun sistem: dalak, tonsiller, timus - microglia, makrofaj, mast hücresi, vb. Kannabinoid reseptörlerinin sinyal ileti mekanizmaları Mekanizma Reseptör Gi/O protein aktivasyonu CB1/CB2 Adenilil siklaz inhibisyonu CB1/CB2 Kalsiyum kanallarının blokajı CB1 Potasyum kanallarının aktivasyonu CB1 MAPK aktivasyonu CB1/CB2 Kannabinoid tetradı Lokomotor aktivitede Hipotermi Katalepsi Analjezi Fizyolojik sistemlere etkiler Santral sinir sistemi Öfori-kannabinoid sarhoşluğu İntellektüel ve
    [Show full text]
  • Analysis of Natural Product Regulation of Cannabinoid Receptors in the Treatment of Human Disease☆
    Analysis of natural product regulation of cannabinoid receptors in the treatment of human disease☆ S. Badal a,⁎, K.N. Smith b, R. Rajnarayanan c a Department of Basic Medical Sciences, Faculty of Medical Sciences, University of the West Indies, Mona, Jamaica b Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA c Jacobs School of Medicine and Biomedical Sciences, Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14228, USA article info abstract Available online 3 June 2017 The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many Keywords: biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review Drug dependence/addiction will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling GTPases as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular Gproteins disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are G protein-coupled receptor also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, Natural products this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural prod- Neurodegenerative disorders ucts given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without unideal side-effects.
    [Show full text]
  • Cannabinoids and the Urinary Bladder
    Bakali and Tincello, Gynecol Obstet 2013, 3:4 Gynecology & Obstetrics http://dx.doi.org/10.4172/2161-0932.1000163 Review Article Open Access Cannabinoids and the Urinary Bladder Evangelia Bakali1,2* and Douglas G Tincello1,2 1University Hospitals of Leicester, NHS trust, Leicester, UK 2Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, UK Abstract The presence of the Endocannabinoid System (ECS) in the urinary bladder has led to speculation that endocannabinoid-signalling is involved in the signal transduction pathways regulating bladder relaxation and may be involved in pathophysiological processes of the bladder. On the basis of this evidence, it was postulated that the binding of endocannabinoids to the cannabinoid receptors (CB1 and CB2) may result in relaxation of the urinary bladder during the filling phase. Dysregulation of the ECS in human bladder may be responsible for the aetiopathogenesis of Overactive Bladder Syndrome (OAB) and Detrusor Overactivity (DO). Keywords: Cannabinoids; Endocannabinoids; Cannabinoid haemorrhage, menopausal symptoms and urinary symptoms [8]. receptors; Endocannabinoid system More common therapeutic applications of cannabis include analgesia, migraine, muscle spasms, seizures, attenuation of nausea and vomiting Introduction of cancer chemotherapy, anti-rheumatic and antipyretic actions [8,9]. Over the past decade, interest in the role of endocannabinoids The pharmacological effects of cannabinoids are mediated by two in regulating many mammalian processes has increased and has types of G Protein-Coupled Receptors (GPCR) called CB1 and CB2. CB1 been proposed to be involved in the signal transduction mechanism was first identified in 1988 and subsequently cloned from rat cerebral regulating micturition [1,2]. In a sub-analysis of a multicentre, cortex in 1990 [10,11].
    [Show full text]
  • Cb2 Cannabinoid Receptors: New Vistas
    CB2 CANNABINOID RECEPTORS: NEW VISTAS The first International Conference devoted to studies of the CB2 cannabinoid receptor Organised by: Keith A. Sharkey, Canada (Chair) Marnie Duncan, Canada Ken Mackie, USA Ruth Ross, UK Betty Yao, USA Cover art by Sandra Sharkey: Cloudy peak (2007). Sponsors The organisers express their gratitude to the following agencies and companies for the generous support of the CB2 Cannabinoid Receptors conference. ACKNOWLEDGEMENTS The organisers of the CB2 receptor conference would like to thank the following individuals for their contributions to the success of this event. University of Calgary Robin Fisher Kevin Ho Marlene Manson The Banff Centre Michiko Ellis Edward Marran Special thanks Sandra Sharkey The Banff Centre locations Registration Daily Program All presentations are in the Max Bell Building. Thursday, May 31 Arrival 2.30 - Registration (Max Bell Foyer) 5.30 p.m. 5.30 – Buffet dinner (Banff Centre Dining Room) 7:00 p.m. 7.15 - Welcome to Banff – Dr. Keith Sharkey, University of Calgary 7.30 p.m. 7.30 - Keynote address: 8.30 p.m. The enzymatic regulation of Dr. Benjamin Cravatt endocannabinoid signaling – our state of Scripps Research Institute understanding and the future challenges that remain 8.30 - Opening reception / mixer 10:00 p.m. Friday, June 1 7:00 - Breakfast (Banff Centre Dining Room) 8:00 a.m. Session I Structural and molecular determinants of CB2 receptors and CB2 receptor signaling Session Moderator: Dr. Alex Makriyannis, Northeastern University 8:15 – Opening remarks – Dr. Ken Mackie, Indiana University 8:30 a.m. 8:30 – Pharmacological interactions between Dr. Roger Pertwee 9:00 a.m.
    [Show full text]
  • Cannabinoid CB2 Receptor Ligand Profiling Reveals Biased Signalling
    ARTICLE Received 17 Mar 2016 | Accepted 15 Nov 2016 | Published 3 Jan 2017 DOI: 10.1038/ncomms13958 OPEN Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity Marjolein Soethoudt1,2,*, Uwe Grether3,*, Ju¨rgen Fingerle4, Travis W. Grim5, Filomena Fezza6,7, Luciano de Petrocellis8, Christoph Ullmer3, Benno Rothenha¨usler3, Camille Perret3, Noortje van Gils2, David Finlay9, Christa MacDonald9, Andrea Chicca10, Marianela Dalghi Gens10, Jordyn Stuart11, Henk de Vries2, Nicolina Mastrangelo12, Lizi Xia2, Georgios Alachouzos1, Marc P. Baggelaar1, Andrea Martella1,2, Elliot D. Mock1, Hui Deng1, Laura H. Heitman2,**, Mark Connor11,**, Vincenzo Di Marzo8,**, Ju¨rg Gertsch10,**, Aron H. Lichtman5,**, Mauro Maccarrone7,12,**, Pal Pacher13, Michelle Glass9 & Mario van der Stelt1 The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research. 1 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
    [Show full text]
  • Cannabinoids and the Endocannabinoid System
    Cannabinoids 2006;1(1):10-14 Mini-review Cannabinoids and the Endocannabinoid System Franjo Grotenhermen nova-Institut, Goldenbergstraße 2, D-50354 Hürth, Germany Abstract The human body possesses specific binding sites on the surface of many cell types for cannabi- noids, and our body produces several endocannabinoids, fatty acid derivatives that bind to these cannabinoid receptors (CB) and activate them. CB receptors and endocannabinoids together con- stitute the endocannabinoid system. Some phytocannabinoids, cannabinoids of the cannabis plant, and a multitude of synthetic cannabinoids produced in the laboratory mimic the effects of endo- cannabinoids. ∆9-THC (dronabinol), the pharmacologically most active cannabinoid of the canna- bis plant, binds to both types of cannabinoid receptors that have been identified so far, the CB1 and the CB2 receptor. These receptors have been found in the central nervous system (brain and spinal cord) and many peripheral tissues and organs. Depending on the kind of cells, on dose and state of the body, activation of CB receptors may cause a multitude of effects including euphoria, anxiety, dry mouth, muscle relaxation, hunger and pain reduction. Besides activation of CB receptors sev- eral other approaches are under investigation to influence the cannabinoid system with therapeutic intent, including blockade of CB receptors (antagonism) and modulation of endocannabinoid con- centrations by inhibition of their degradation. Currently, several preparations that stimulate can- nabinoid receptors (dronabinol, nabilone and cannabis) and one compound that blocks the CB1 re- ceptor (rimonabant) are used medicinally. Keywords: Cannabis, THC, cannabinoid, cannabinoid receptor, endocannabinoid, therapeutic use. This article can be downloaded, printed and distributed freely for any non-commercial purposes, provided the original work is prop- erly cited (see copyright info below).
    [Show full text]
  • Medicinal Marijuana Petition (N.J.A.C
    New Jersey Department of Health Medicinal Marijuana Program PO 360 Trenton, NJ 08625~360 MEDICINAL MARIJUANA PETITION (N.J.A.C. 8:64-5.1 et seq.) INSTRUCTIONS This petftion form is to be used only for requesting approval of an addftional medical condftion or treatment thereof as a "debilftating medical condftion" pursuant to the New Jersey Compassionete Use Medical Marijuana Act, N.J. S.A. 24:61-3. Only one condition or treatment may be identiffed per petftion form. For addftional condftions or treatments, a separate petftion form must be submftted. NOTE: This Petition fann tracks the requirements of N.J..A.C. 8:64-5.3. Note that if a petition does not contain all information required by N.J..A.C. 8:64-5.3, the Department will deny the petition and. retum it to petitioner without further review. For that reason the Department strongly encourages use of the Petition form. This completed petftion must be postmarked August 1 through August 31, 2016 and sent by certified mail to: New Jersey Department of Heaffh Office of Commissioner - Medicinal Marijuana Program Attention: Michele Stark 369 South Warren Street Trenton, NJ 08608 Please complete each section of this petition. If there are any supportive documents attached to this petftion, you should reference those documents in the text of/he petftion. If you need addftional space for any item, please use a separate piece of paper, number the ftem accordingly, and attach ft to the petftion. 1. Petitioner In mation Name: Street Address: , City, State, Zip Code: Telephone Number Email Address: 2.
    [Show full text]
  • Cannabinoids and the Urinary Bladder
    logy & Ob o st ec e tr n i y c s G Bakali and Tincello, Gynecol Obstet 2013, 3:4 Gynecology & Obstetrics DOI: 10.4172/2161-0932.1000163 ISSN: 2161-0932 Review Article Open Access Cannabinoids and the Urinary Bladder Evangelia Bakali1,2* and Douglas G Tincello1,2 1University Hospitals of Leicester, NHS trust, Leicester, UK 2Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, UK Abstract The presence of the Endocannabinoid System (ECS) in the urinary bladder has led to speculation that endocannabinoid-signalling is involved in the signal transduction pathways regulating bladder relaxation and may be involved in pathophysiological processes of the bladder. On the basis of this evidence, it was postulated that the binding of endocannabinoids to the cannabinoid receptors (CB1 and CB2) may result in relaxation of the urinary bladder during the filling phase. Dysregulation of the ECS in human bladder may be responsible for the aetiopathogenesis of Overactive Bladder Syndrome (OAB) and Detrusor Overactivity (DO). Keywords: Cannabinoids; Endocannabinoids; Cannabinoid haemorrhage, menopausal symptoms and urinary symptoms [8]. receptors; Endocannabinoid system More common therapeutic applications of cannabis include analgesia, migraine, muscle spasms, seizures, attenuation of nausea and vomiting Introduction of cancer chemotherapy, anti-rheumatic and antipyretic actions [8,9]. Over the past decade, interest in the role of endocannabinoids The pharmacological effects of cannabinoids are mediated by two in regulating many mammalian processes has increased and has types of G Protein-Coupled Receptors (GPCR) called CB1 and CB2. CB1 been proposed to be involved in the signal transduction mechanism was first identified in 1988 and subsequently cloned from rat cerebral regulating micturition [1,2].
    [Show full text]
  • Brain CB2 Receptors: Implications for Neuropsychiatric Disorders
    Pharmaceuticals 2010, 3, 2517-2553; doi:10.3390/ph3082517 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review Brain CB2 Receptors: Implications for Neuropsychiatric Disorders Michelle Roche 1,* and David P Finn 2 1 Physiology, School of Medicine, NCBES Neuroscience Cluster and Centre for Pain Research, National University of Ireland, Galway, University Road, Galway, Ireland 2 Pharmacology and Therapeutics, School of Medicine, NCBES Neuroscience Cluster and Centre for Pain Research, National University of Ireland, Galway, University Road, Galway, Ireland; E-Mail: [email protected] (D.P.F.) * To whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +353 91 495427; Fax: +353 91 494544. Received: 15 July 2010; in revised form: 4 August 2010 / Accepted: 9 August 2010 / Published: 10 August 2010 Abstract: Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB2 receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons. Expression of the CB2 receptor in the brain is significantly lower than that of the CB1 receptor. Conflicting findings have been reported on the neurological effects of pharmacological agents targeting the CB2 receptor under normal conditions. Under inflammatory conditions, CB2 receptor expression in the brain is enhanced and CB2 receptor agonists exhibit potent anti-inflammatory effects. These findings have prompted research into the CB2 receptor as a possible target for the treatment of neuroinflammatory and neurodegenerative disorders. Neuroinflammatory alterations are also associated with neuropsychiatric disorders and polymorphisms in the CB2 gene have been reported in depression, eating disorders and schizophrenia.
    [Show full text]
  • Effects of Cannabinor, a Novel Selective Cannabinoid 2 Receptor Agonist, on Bladder Function in Normal Rats
    EUROPEAN UROLOGY 57 (2010) 1093–1100 available at www.sciencedirect.com journal homepage: www.europeanurology.com Voiding Dysfunction Effects of Cannabinor, a Novel Selective Cannabinoid 2 Receptor Agonist, on Bladder Function in Normal Rats Christian Gratzke a,b,f, Tomi Streng c, Christian G. Stief b, Thomas R. Downs d, Iris Alroy e, Jan S. Rosenbaum d, Karl-Erik Andersson f,*, Petter Hedlund a,g a Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden b Department of Urology, Ludwig-Maximilians-University, Munich, Germany c Department of Pharmacology, Turku University, Turku, Finland d Women’s Health, Procter & Gamble Health Care, Cincinnati, OH, USA e Pharmos Limited, Rehovot, Israel f Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA g Urological Research Institute, San Raffaele University Hospital, Milan, Italy Article info Abstract Article history: Background: Cannabinoid (CB) receptors may be involved in the control of bladder Accepted February 19, 2010 function; the role of CB receptor subtypes in micturition has not been established. Published online ahead of Objectives: Our aim was to evaluate the effects of cannabinor, a novel CB2 receptor print on March 1, 2010 agonist, on rat bladder function. Design, setting, and participants: Sprague Dawley rats were used. Distribution of Keywords: CB2 receptors in sensory and cholinergic nerves of the detrusor was studied. Cannabinoid Selectivity of cannabinor for human and rat CB receptors was evaluated. Effects Urothelium of cannabinor on rat detrusor and micturition were investigated. Sensory Measurements: Immunohistochemistry, radioligand binding, tritium outflow Detrusor assays, organ bath studies of isolated bladder tissue, and cystometry in awake Cystometry rats were used.
    [Show full text]