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Cannabinoid Receptors

Cannabinoid receptors derive their name from Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive principle in Cannabis sativa (marijuana). Although marijuana has been in use for over 4,000 years as a therapeutic agent and as a recreational drug, it was not until the 1980s that evidence revealed a receptor-based mechanism of action. Δ9-THC was shown to modulate cAMP formation and a binding site for the high affinity cannabinoid agonist, CP-55,940, was identified in mammalian brain.

In 1990, the first cannabinoid receptor, CB1, was cloned and classified as a member of the family of G protein-coupled receptors. The CB1 cannabinoid receptor is found in high abundance in brain neurons, with highest levels expressed in basal ganglia, cerebellum, hippocampus and cerebral cortex. Considerably lower expression is found in peripheral tissue, including lung, testis, uterus, and vascular tissue. Following agonist binding, CB1 receptors couple to the inhibition of adenylyl cyclase, inhibition of N- and Q-type voltage-operated calcium channels, and stimulation of inwardly rectifying and A type potassium channels.

A second cannabinoid receptor, CB2, was cloned in 1993 with 44% identity at the amino acid level to the CB1 receptor. The CB2 receptor is found primarily in cells of the peripheral immune system with sparse expression in neurons and immune cells of the CNS. The CB2 receptor is coupled to inhibition of adenylyl cyclase, but does not appear to couple to ion channel regulation. A third and apparently rare human cannabinoid receptor, CB1A, is an alternatively spliced form of the human CB1 receptor characterized by a loss of 28 amino acids from the N terminus. This shorter mRNA may be poorly transcribed in humans and does not appear to be expressed in rat or mouse. It should be noted that IUPHAR nomenclature, if applied to these receptors, might result in the renaming of the CB1 receptor to CB1a and the splice variant would then become CB1b. Pharmacological evidence suggests additional cannabinoid-like receptors exist that have yet to be identified at the molecular level.

Many cannabinoid receptor agonists have been synthesized and extensively studied, including analogs of the tricyclic benzopyran Δ9-THC, such as HU-210, the bicyclic analogs typified by CP-55,940, and the amino-alkylindoles such as WIN 55,212-2. Both receptors have essentially equal affinity for many cannabinoid agonists including Δ 9-THC, CP-55,940, HU-210, WIN 55,212-2, levonantradol and nabilone. Selective agonists and antagonists have been synthesized for both the CB1 and CB2 receptors (see accompanying table) providing useful pharmacological tools that compliment the available CB1, CB2 and CB1\CB2 knockout mice.

Analogous to the discovery of the endogenous opiate receptor agonists, enkephalin and endorphin, the presence of cannabinoid receptors suggested that endogenous cannabinoids might be present in mammalian brain. The lipid N-arachidonoyl-ethanolamide (anandamide) and subsequently 2-arachidonoyl-glycerol (2-AG), 2-arachidonoyl-glyceryl ether (2-AGE), N-arachidonoyl-dopamine (NADA), and O-arachidonoyl-ethanolamine (virhodamine) were isolated from mammalian tissue and were shown to be functional cannabinoid receptor agonists. Anandamide fulfills all the requirements to be classified as a neurotransmitter except that it appears to be stored as a phospholipid precursor that is released by calcium-dependent phospholipase D enzymatic cleavage. An energy- and ion-independent transport of anandamide into neurons has been characterized, but not identified at the molecular level. Intracellular fatty acid amidohydrolase (FAAH) splits anandamide into arachidonic acid and ethanolamine that provides the chemical gradient to allow the specific transport of anandamide across the plasma membrane. The storage, release, metabolism and physiological role of these and possibly other lipid neurotransmitters are currently under intense investigation. Recent studies have shown that the transient suppression of GABA-mediated transmission following depolarization of hippocampal pyramidal neurons is mediated by retrograde signaling through the release of endogenous cannabinoids. Similar retrograde signaling has been observed in modulation of dopamine and glutamate release. Signaling by the endocannabinoid system may thus represent a feedback mechanism by which postsynaptic neurons can modulate presynaptic output.

Cannabinoids have been shown to possess therapeutic potential in the treatment of emesis, cachexia, pain, muscle spasms, and other conditions, but psychotropic side effects preclude their widespread use. Development of high affinity and selective orthosteric or allosteric cannabinoid receptor ligands, restricting CNS penetration, or modulation of endocannabinoid concentrations by targeting the transporter, phospholipase D or FAAH proteins, may improve the therapeutic potential of modulating the cannabinoid receptor system.

The Table below contains accepted modulators and additional information. For a list of additional products, see the Materials section below.


ACEA: (all Z)-N-(2-Cycloethyl)-5,8,11,14-eicosatetraenamide
AM251: N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
AM630: 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl] (4-methoxyphenyl) methanone
AM281: N-(Morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide
CP-55,940: (–)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol)
HU 210: (–)-11-Hydroxy-delta(8)-tetrahydrocannabinol-dimethylheptyl
HU 243: (6aR,9R,10aR)-3-(1,1-Dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol
JWH-015: (2-Methyl-1-propyl-1H-indol-3-yl)-1-naphthalenyl-methanone
JWH-133: (3-(1′ 1′ Dimethylbutyl)-1-deoxy-D8-tetrahydrocannabinol
LY-320135: 4-[6-Methoxy-2-(4-methoxy-phenyl)-benzofuran-3-carbonyl]-benzonitrile
O-1812: (R)-(20-Cyano-16,16-dimethyl docosa-cis-5,8,11,14-tetraeno)-1'-hydroxy-2'-propylamine
SR 141716A: N-Piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide
SR 144528: N-[(1S)-endo-1,3,3-Trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methoxybenzyl)-pyrazole-3-carboxamide
Δ 9-THC: Δ9-Tetrahydrocannabinol
WIN 55,212-2: [2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone



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