Article Figures & Data
Figures
- Figure 1
The structures of four constituents of cannabis: Δ9-THC, Δ8-THC, cannabinol, and cannabidiol.
- Figure 2
The structures of the synthetic classical cannabinoid receptor agonists, HU-210 and desacetyl-l-nantradol, and of HU-211, the (+)-enantiomer of HU-210.
- Figure 3
The structures of the CB2-selective cannabinoid receptor agonists, HU-308, L-759633, L-759656, JWH-133, JWH-139, and JWH-051.
- Figure 4
The structures of the (−)-enantiomers of three nonclassical cannabinoid receptor agonists: CP55940, CP47497, and CP55244.
- Figure 5
The structures of three aminoalkylindole cannabinoid receptor agonists: R-(+)-WIN55212, JWH-015, and L-768242.
- Figure 6
The structures of five endogenous cannabinoids.
- Figure 7
The structures of the CB1-selective synthetic cannabinoid receptor agonists, methanandamide, ACEA, ACPA, and O-1812.
- Figure 8
The structures of the cannabinoid receptor antagonists/inverse agonists, SR141716A, AM251, AM281, SR144528, and LY320135.
- Figure 9
The structures of the pravadoline analogs, AM630, WIN56098, and WIN54461 (6-bromopravadoline).
- Figure 10
The structures of O-1184 and O-1238.
- Figure 11
Amino acid sequence alignment of human, rat, and mouse CB1 and CB2 receptors. Consensus matches are boxed and shaded with darker shading for identities and lighter shading for conservative substitutions. Numbering corresponds to the rat/mouse CB1 sequence. Underlines indicate the positions of the seven transmembrane helices. Helix 3 spans two lines as indicated by the arrowheads on the underline. The rat CB2sequence is a consensus of GenBank accession nos. AF286721 and AF176350together with edited trace data from the rat genome sequencing project (http://www.ncbi.nlm.nih.gov/genome/seq/RnBlast.html). The rat CB2 residue at alignment position 310 appears to be polymorphic [i.e., either Ala (as shown) or Thr].
- Figure 12
Autoradiographs show cannabinoid receptor binding (a, f, g) and CB1 (b, d) and CB2 (c, e) mRNA expression in sections from the mouse (sagittal) and human brain (coronal) and mouse spleen (M. Herkenham and A. Hohmann, unpublished observations). Receptor binding of [3H]CP55940, a high-affinity agonist, shows high levels of receptors in the basal ganglia, cerebellum, hippocampus (hipp), and cerebral cortex (a). Cells expressing CB1 mRNA are shown in a similar plane of section (b). Lack of detectable CB2 expression in brain (c) indicates that the binding is to the CB1 type. In contrast, spleen has the opposite relative abundance of CB1 (d) versus CB2 mRNA (e) expression. The human brain has a distribution of cannabinoid receptors that closely matches that of the mouse, with high levels expressed in the basal ganglia, intermediate levels in the amygdala and hypothalamus, and low levels in the thalamus (f, g). The high levels of binding in many areas [cerebellar molecular layer, globus pallidus (GP, GPe), entopeduncular nucleus (Ep, GPi), substantia nigra pars reticulata (SNR), and dentate gyrus molecular layer] are on axons of cells expressing mRNA in afferent areas, such as the caudate putamen (CPu). Some cells in cortex and hippocampus express extremely high levels of CB1 message (arrows in b). Bars measure 1 mm for mouse and 1 cm for human.
- Figure 13
Electron micrograph of consecutive rat brain hippocampal sections stained with the C terminus-CB1antibody showing that inhibitory terminals presynaptically express CB1 cannabinoid receptors in the hippocampus. Serial sections have been cut through a CB1-immunoreactive axon terminal forming a symmetrical (GABAergic) synapse (thick arrow) on a dendrite in the stratum radiatum of the CA1 region. Gold particle labeling (small arrows) is restricted to the inner surface of the bouton, where the intracellular carboxy terminus epitope of CB1 is located. A small arrowhead indicates a dense core vesicle. In contrast, the complete lack of staining in axon terminals (★), forming an asymmetrical synapse (large arrowhead), suggests that glutamatergic axons do not contain CB1 receptors. Scale bar is 0.2 μm. Courtesy of I. Katona and T. F. Freund.
- Figure 14
The structures of abnormal cannabidiol and O-1602.
Tables
Coverage Authors Pharmacology, coupling, localization Howlett, 1995a,b;Pertwee, 1997; Felder and Glass, 1998; Ameri, 1999 Agonists and antagonists Barth and Rinaldi-Carmona, 1999; Pertwee, 1999 Signal transduction Howlett and Mukhopadhyay, 2000 Localization and function of CB1 receptors in the central nervous system Elphick and Egertová, 2001 Molecular biology Onaivi et al., 1996; Matsuda, 1997 Molecular modeling Reggio, 1999 Regulation of immune response, coupling Berdyshev, 2000; Cabral, 2001 Biochemistry and pharmacology of the endocannabinoids Mechoulam et al., 1998; Di Marzo et al., 1999; Martin et al., 1999; Palmer et al., 2000; Reggio and Traore, 2000 Behavioral effects of cannabinoids in animals Chaperon and Thiebot, 1999 Cannabinoid receptors and neurotransmitter release Schlicker and Kathman, 2001 Cannabinoid receptors and pain Martin and Lichtman, 1998; Pertwee, 2001b Therapeutic potential Pertwee, 2000b; Piomelli et al., 2000;Porter and Felder, 2001 - Table 2
Ki values of certain ligands for the in vitro displacement of [3H]CP55940, [3H]R-(+)-WIN55212, or [3H]HU-243 from CB1- and CB2-specific binding sites
Ligand CB1KiValue CB2Ki Value Reference nM CB1-selective ligands in order of decreasing CB1/CB2 selectivity ACEA 1.42-a 2-b >2,0002-a 2-b Hillard et al., 1999 O-1812 3.42-b 3,8702-b Di Marzo et al., 2001a SR141716A 11.8 13,200 Felder et al., 1998 11.8 973 Felder et al., 1995 12.3 702 Showalter et al., 1996 5.6 >1,000 Rinaldi-Carmona et al., 1994 1.982-b >1,0002-b Rinaldi-Carmona et al., 1994 AM281 122-b 4,2002-c Lan et al., 1999a ACPA 2.22-a 2-b 7152-a 2-b Hillard et al., 1999 2-Arachidonylglyceryl ether 21.22-b >3,000 Hanus et al., 2001 LY320135 141 14,900 Felder et al., 1998 R-(+)-methanandamide 17.92-a 2-b 8682-a 2-c Lin et al., 1998 202-a 2-b 8152-c Khanolkar et al., 1996 Ligands without any marked CB1/CB2 selectivity Anandamide 612-a 2-b 1,9302-a 2-c Lin et al., 1998 892-a 3712-a Showalter et al., 1996 543 1,940 Felder et al., 1995 71.72-a 2-b 2792-a 2-b Hillard et al., 1999 2522-b 581 Mechoulam et al., 1995 2-Arachidonoylglycerol 4722-b 1,400 Mechoulam et al., 1995 58.32-d 1452-d Ben-Shabat et al., 1998 HU-210 0.0608 0.524 Felder et al., 1995 0.12-b 0.17 Rhee et al., 1997 0.73 0.22 Showalter et al., 1996 CP55940 5 1.8 Ross et al., 1999a 3.72 2.55 Felder et al., 1995 1.372-b 1.372-b Rinaldi-Carmona et al., 1994 0.58 0.69 Showalter et al., 1996 0.502-a 2-b 2.802-a 2-b Hillard et al., 1999 Δ9-THC 53.3 75.3 Felder et al., 1995 39.52-b 40 Bayewitch et al., 1996 40.7 36.4 Showalter et al., 1996 80.32-b 32.2 Rhee et al., 1997 35.32-b 3.92-b Rinaldi-Carmona et al., 1994 Δ8-THC 47.62-b 39.32-c Busch-Petersen et al., 1996 R-(+)-WIN55212 9.942-b 16.22-b Rinaldi-Carmona et al., 1994 4.42-a 2-b 1.22-a 2-b Hillard et al., 1999 1.89 0.28 Showalter et al., 1996 62.3 3.3 Felder et al., 1995 123 4.1 Shire et al., 1996a CB2-selective ligands in order of increasing CB2/CB1 selectivity JWH-015 383 13.8 Showalter et al., 1996 JWH-051 1.22-b 0.032 Huffman et al., 1996 L-768242 1,917 12 Gallant et al., 1996 JWH-139 2,2902-b 14 Huffman et al., 1998 AM 630 5,152 31.2 Ross et al., 1999a JWH-133 6772-b 3.4 Huffman et al., 1999 L-759633 1,043 6.4 Ross et al., 1999a 15,850 20 Gareau et al., 1996 L-759656 4,888 11.8 Ross et al., 1999a >20,000 19.4 Gareau et al., 1996 HU-308 >10,0002-b 22.7 Hanus et al., 1999 SR144528 437 0.60 Rinaldi-Carmona et al., 1998 3052-b 0.302-b Rinaldi-Carmona et al., 1998 >10,000 5.6 Ross et al., 1999a DMH, dimethylheptyl.
↵2-a With phenylmethylsulfonyl fluoride.
↵2-b Binding to rat cannabinoid receptors on transfected cells or on brain (CB1) or spleen tissue (CB2).
↵2-c Binding to mouse spleen cannabinoid receptors.
↵2-d Species unspecified. All other data from experiments with human cannabinoid receptors.
- Table 3
CB1 and CB2 Ki values of stereoisomers of cannabidiol and of two cannabidiol analogs
Ligand CB1Ki Value CB2Ki Value Reference nM (−)-CBD 4,350 2,860 Showalter et al., 1996 >10,000 >10,000 Bisogno et al., 2001 (+)-CBD 842 203 Bisogno et al., 2001 (−)-5′-DMH-CBD >10,000 1,800 Bisogno et al., 2001 (+)-5′-DMH-CBD 17.4 211 Bisogno et al., 2001 (−)-7-OH-5′-DMH-CBD 4,400 671 Bisogno et al., 2001 (+)-7-OH-5′-DMH-CBD 2.5 44 Bisogno et al., 2001 DMH, dimethylheptyl.
Position4-a Variants4-bNumber/Total Consensus Variants4-b Domain 53 9 /59 F Y Amino terminal 66 2 /59 D E Amino terminal 67 25 /29 N S,T,H Amino terminal 68 22 /59 P A,S,T Amino terminal 69 4 /59 Q P Amino terminal 71 4 /59 V G,I,A Amino terminal 73 12 /59 A G,V,S Amino terminal 74 4 /59 D G,V,A Amino terminal 75 20 /59 — P,D Amino terminal 76 20 /59 Q G,T,A,— Amino terminal 77 15 /58 V L,A,T,G,I Amino terminal 79 21 /59 I L,M,V Amino terminal 83 2 /59 Y F,L Amino terminal 90 12 /60 F Y Amino terminal 94 21 /60 E D,G,— Amino terminal 106 4 /60 M I Amino terminal 111 4 /60 I V Amino terminal 176 4 /60 V I Extracellular end of TM1 187 5 /60 P R,H Extracellular, adjacent to TM3 259 4 /60 K E Extracellular, adjacent to TM4 262 6 /60 Q K,R Extracellular, between TM4 and TM5 271 4 /60 L H Extracellular, between TM4 and TM5 286 2 /54 T S TM5 312 2 /53 R P Intracellular, between TM5 and TM6 Cell Type/Tissue Species Receptor Type Method of Detection B lymphocytes Human CB2 RT-PCR5-aor confocal microscopy5-b Macrophages Human, mouse, rat CB2 RT-PCR5-a 5-c 5-d Mast cells Rat CB2 RT-PCR5-e Microglia Rat CB1, CB2 Mutational RT-PCR,5-d 5-f Western immunoblot,5-d 5-f or immunocytochemistry5-f 5-g Natural killer cells Human CB2 RT-PCR5-a Peripheral mononuclear cells Human, rat CB2 RT-PCR5-a 5-e CD4 lymphocytes Human CB2 RT-PCR5-a CD8 lymphocytes Human CB2 RT-PCR5-a Lymph nodes Human CB2 RT-PCR5-a Peyer's patches Rat CB5-150 Radioligand binding5-h or radioligand autoradiography5-h Spleen Human, mouse, rat CB1, CB2 Radioligand binding,5-h 5-i radioligand autoradiography,5-h Northern blot,5-j in situ hybridization,5-j or RT-PCR5-a 5-e Tonsils Human CB2 RT-PCR5-aor immunocytochemistry5-a Thymus Human CB2 RT-PCR5-a Transmitter Tissue Preparation or Brain Area Transmitter-Releasing Stimulus References In vivo ACh6-a Rat medial-prefrontal cortex None Gessa et al., 1998a Rat hippocampus None —6-b GABA6-c Rat striatum None Tersigni and Rosenberg, 1996 In vitro ACh Rat hippocampal slices ES —6-d Rat hippocampal & frontal cortical synaptosomes K+ or Ca2+ Gifford et al., 2000 Mouse hippocampal or cerebrocortical slices ES or Ca2+ —6-e Guinea pig intestinal tissue (MPLM) ES —6-f NA Guinea pig cerebrocortical slices ES Schlicker et al., 1997 Human and guinea pig hippocampal slices ES or Ca2+ Schlicker et al., 1997 Guinea pig hippocampal slices NMDA or kainate Kathmann et al., 1999a Guinea pig hypothalamic slices ES Schlicker et al., 1997 Guinea pig cerebellar slices ES Schlicker et al., 1997 Guinea pig retinal discs ES or Ca2+ Schlicker et al., 1996 Guinea pig bronchial slices ES Vizi et al., 2001 Human atrial appendage segments ES Molderings et al., 1999 Rat atria ES Ishac et al., 1996 Rat heart ES Kurihara et al., 2001 Rat vas deferens ES Ishac et al., 1996 Mouse vas deferens ES Trendelenburg et al., 2000 Mouse cultured sympathetic neurons ES Göbel et al., 2000 DA Rat striatal slices NMDA Kathmann et al., 1999a Rat striatal slices ES Cadogan et al., 1997 Guinea pig retinal discs ES Schlicker et al., 1996 5-HT Mouse cerebrocortical slices ES or Ca2+ Nakazi et al., 2000 Mouse hypothalamic slices ES Kathmann et al., 1999b GABA Human hippocampal slices ES Katona et al., 2000 Rat hippocampal slices ES Katona et al., 1999 GABA6-c Rat or mouse hippocampal slices ES —6-g Slices of rat or mouse amygdala (BLC) ES Katona et al., 2001 1y cultures of neonatal rat hippocampal cells None Irving et al., 2000 1y cultures of neonatal rat hippocampal cells ES Ohno-Shosaku et al., 2001 Rat striatal slices ES Szabo et al., 1998 Rat midbrain slices (SNR) ES —6-h Rat brain slices (RVM) ES Vaughan et al., 1999 Rat cerebellar slices None Takahashi and Linden, 2000 Rat cerebellar slices ES Kreitzer and Regehr, 2001b Rat brain slices (PAG) ES Vaughan et al., 2000 Rat brain slices (shell region of NAc) ES Hoffman and Lupica, 2001 Mouse brain slices (NAc) ES Manzoni and Bockaert, 2001 Rat spinal trigeminal nucleus pars caudalis (SG) ES Jennings et al., 2001 Guinea pig intestinal tissue (MPLM) Ethylenediamine Begg et al., 2002 Glu6-c Rat prefrontal cortical slices ES Auclair et al., 2000 Rat brain slices (PAG) ES Vaughan et al., 2000 Mouse brain slices (NAc) ES Robbe et al., 2001 1y cultures of rat hippocampal cells Low [Mg2+]o —6-i 1y cultures of rat hippocampal cells ES Sullivan, 1999 Mouse hippocampal slices6-j ES —6-k Rat or mouse cerebellar slices ES —6-l Rat striatal slices ES —6-m Rat midbrain slices (SNR) ES Szabo et al., 2000 Rat spinal cord slices (SG) ES Morisset and Urban, 2001 1y cultures of rat cerebellar granule cells Low [Mg2+]o Irving et al., 2001 Gly6-c Rat spinal trigeminal nucleus pars caudalis (SG) ES Jennings et al., 2001 d-Asp 1y cultures of rat cerebellar granule cells K+ Breivogel et al., 1999 CCK Rat hippocampal slices K+ Beinfeld and Connolly, 2001 ES, electrical stimulation; [Mg2+]o, extracellular magnesium concentration; MPLM, myenteric plexus-longitudinal muscle preparation; BLC, basolateral complex; NAc, nucleus accumbens; PAG, periaqueductal gray; RVM, rostral ventromedial medulla; SG, substantia gelatinosa; SNR, substantia nigra pars reticulata; ACh, acetylcholine; DA, dopamine; d-Asp,d-aspartate; NA, noradrenaline; 1y, primary.
↵6-a ACh collected by microdialysis.
↵6-b Gessa et al., 1997, 1998a; Carta et al., 1998; Nava et al., 2000, 2001.
↵6-c Indirect electrophysiological evidence for decreased transmitter release: in some of these investigations, there was also evidence that cannabinoids inhibited spontaneous as well as evoked release of GABA or Glu.
↵6-d Gifford and Ashby, 1996; Gifford et al., 1997a,b; 1999; Kathmann et al., 2001a.
↵6-e Nakazi et al., 2000; Kathmann et al., 2001a,b.
↵6-f Pertwee et al., 1996; Coutts and Pertwee, 1997; Mang et al., 2001.
↵6-g Hájos et al., 2000, 2001;Hoffman and Lupica, 2000; Wilson and Nicoll, 2001.
↵6-h Chan and Yung, 1998; Chan et al., 1998.
↵6-i Shen et al., 1996; Shen and Thayer, 1998a,b; 1999.
↵6-j Signs ofR-(+)-WIN55212-induced inhibition of glutamate release have been observed in tissue from both wild-type and CB1 −/− mice.
↵6-k Misner and Sullivan, 1999;Hájos et al., 2001.
↵6-l Lévénès et al., 1998; Kreitzer and Regehr, 2001a; Maejima et al., 2001.
↵6-m Gerdeman and Lovinger, 2001; Huang et al., 2001.
In this issue
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- Article
- Abstract
- I. Introduction: Overview of the Cannabinoid Receptors
- II. Classification of Ligands That Bind to Cannabinoid Receptors
- III. Bioassay
- IV. Cellular Signal Transduction
- V. Molecular Biology of Cannabinoid Receptors
- VI. Cannabinoid Receptor Knockout Mice
- VII. Tissue Distribution of Cannabinoid Receptors
- VIII. Effects on Neurotransmission
- IX. Immunological Effects
- X. Anandamide Is a Vanilloid Receptor Agonist
- XI. Preliminary Pharmacological Evidence for Non-CB1, Non-CB2 Cannabinoid Receptors
- XII. Conclusions
- Footnotes
- Abbreviations
- References
- Figures & Data
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- eLetters