Isolation and structure elucidation of most of the major cannabinoid constituents — including Δ9-tetrahydrocannabinol (Δ9-THC), which is the principal psychoactive molecule in Cannabis sativa — was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.
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Mechoulam, R. in Cannabinoids as Therapeutic Agents, (ed. Mechoulam, R.), 1–19 (CRC Press Inc., 1986).
O'Shaugnessy, W. B. in The Bengal Dispensatory and Pharmacopoeia, 579 (Bishop's College Press, 1841).
Adams, R. Marihuana. Harvey Lectures 37, 168–197 (1941–1942).
Todd, A. R. Hashish. Experientia 2, 55–60 (1946).
Loewe, S. Cannabiswirkstoffe und Pharmacologie der Cannabinole. Arch. Exp. Pathol. Pharmacol. 211, 175–193 (1950).
Gaoni, Y. & Mechoulam, R. Isolation, structure and partial synthesis of an active constituent of hashish. J. Amer. Chem. Soc. 86, 1646–1647 (1964).
Mechoulam, R., McCallum, N. K. & Burstein, S. Recent advances in the chemistry and biochemistry of cannabis. Chem. Rev. 76, 75–112 (1976).
Agurell, S. et al. Pharmacokinetics and metabolism of Δ-1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol. Rev. 38, 21–43 (1986).
Pertwee, R. G. The ring test: a quantitative method for assessing the 'cataleptic' effect of cannabis in mice. Br. J. Pharmacol. 46, 753–763 (1972).
Pertwee, R. G. Cannabinoid pharmacology: the first 66 years. Br. J. Pharmacol. 147, S163–S171 (2006).
Pertwee, R. G. The central neuropharmacology of psychotropic cannabinoids. Pharmacol. Ther. 36, 189–261 (1988).
Pertwee, R. G. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol. 156, 397–411 (2009).
Mechoulam, R. et al. Stereochemical requirements for cannabinoid activity. J. Med. Chem. 23, 1068–1072 (1980).
Mechoulam, R. et al. Enantiomeric cannabinoids: stereospecificity of psychotropic activity. Experientia 44, 762–764 (1988).
Dewey, W. L. Cannabinoid pharmacology. Pharmacol. Rev. 38, 151–178 (1986).
Hollister, L. E. Health aspects of cannabis. Pharmacol. Rev. 38, 1–20 (1986).
Klee, W. A., Sharma, S. K. & Nirenberg, M. Opiate receptors as regulators of adenylate cyclase. Life Sci. 16, 1869–1874 (1975).
Nathanson, N. M., Klein, W. L. & Nirenberg, M. Regulation of adenylate cyclase activity mediated by muscarinic acetylcholine receptors. Proc. Natl Acad. Sci. USA 75, 1788–1791 (1978).
Sabol, S. L. & Nirenberg, M. Regulation of adenylate cyclase of neuroblastoma x glioma hybrid cells by α-adrenergic receptors. I. Inhibition of adenylate cyclase mediated by α receptors. J. Biol. Chem. 254, 1913–1920 (1979).
Howlett, A. C. & Fleming, R. M. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol. Pharmacol. 26, 532–538 (1984).
Howlett, A. C. Inhibition of neuroblastoma adenylate cyclase by cannabinoid and nantradol compounds. Life Sci. 35, 1803–1810 (1984).
Howlett, A. C. Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. Mol. Pharmacol. 27, 429–436 (1985).
Howlett, A. C., Qualy, J. M. & Khachatrian, L. L. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol. Pharmacol. 29, 307–313 (1986).
Howlett, A. C., Champion, T. M., Wilken, G. H. & Mechoulam, R. Stereochemical effects of 11-OH-Δ 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor. Neuropharmacology 29, 161–165 (1990).
Melvin, L. S. et al. Structure–activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. Mol. Pharmacol. 44, 1008–1015 (1993).
Melvin, L. S., Milne, G. M., Johnson, M. R., Wilken, G. H. & Howlett, A. C. Structure–activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity. Drug Des. Discov. 13, 155–166 (1995).
Devane, W. A., Dysarz F. A. 3rd, Johnson M. R., Melvin L. S. & Howlett A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988).
Gerard, C., Mollereau, C., Vassart, G. & Parmentier, M. Nucleotide sequence of a human cannabinoid receptor cDNA. Nucleic Acids Res. 18, 7142 (1990).
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).
Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).
Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).
Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).
Pertwee, R. G. et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2 . Pharmacol. Rev. 62, 588–631 (2010).
Pamplona, F. A. et al. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc. Natl Acad. Sci. USA 109, 21134–21139 (2012).
Bauer, M. et al. Identification and quantification of a new family of peptide endocannabinoids (pepcans) showing negative allosteric modulation at CB1 receptors. J. Biol. Chem. 287, 36944–36967 (2012).
Heimann, A. S. et al. Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc. Natl Acad. Sci. USA 104, 20588–20593 (2007).
Huffman, J. W. et al. Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J. Med. Chem. 39, 3875–3877 (1996).
Hanuš, L. et al. HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor. Proc. Natl Acad. Sci. USA 96, 14228–14233 (1999).
Anand, P., Whiteside, G., Fowler, C. J. & Hohmann, A. G. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res. Rev. 60, 255–266 (2009).
Fernandez-Ruiz, J., Pazos, M. R., Garcia-Arencibia, M., Sagredo, O. & Ramos, J. A. Role of CB2 receptors in neuroprotective effects of cannabinoids. Mol. Cell. Endocrinol. 286, S91–S96 (2008).
Marriott, K. S. & Huffman, J. W. Recent advances in the development of selective ligands for the cannabinoid CB2 receptor. Curr. Top. Med. Chem. 8, 187–204 (2008).
Pacher, P. & Mechoulam, R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Progr. Lipid Res. 50, 193–211 (2011).
Horváth, B. et al. A new cannabinoid 2 receptor agonist HU-910 attenuates oxidative stress, inflammation, and cell death associated with hepatic ischemia/reperfusion injury. Br. J. Pharmacol. 165, 2462–2478 (2012).
Di Marzo, V., De Petrocellis, L. & Bisogno, T. in Cannabinoids. Handbook of Expermimental Pharmacology (ed. Pertwee, R. G.) 168, 147–185 (Springer, 2005).
Wilson, R. I. & Nicoll R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001).
Vaughan, C. W. & Christie, M. J. in Cannabinoids. Handbook of Expermimental Pharmacology (ed. Pertwee, R. G.) 168, 367–383 (Springer, 2005).
Ohno-Shosaku, T., Tanimura, A., Hashimotodani, Y. & Kano, M. Endocannabinoids and retrograde modulation of synaptic transmission. Neuroscientist 18, 119–132 (2012).
Alger, B. E. Endocannabinoids at the synapse a decade after the dies mirabilis: what we still do not know. J. Physiol. 590, 2203–2212 (2012).
Gregg, L. C. et al. Activation of type 5 metabotropic glutamate receptors and diacylglycerol lipase-α initiates 2-arachidonoylglycerol formation and endocannabinoid-mediated analgesia. J. Neurosci. 32, 9457–9468 (2012).
Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 240–244 (1994).
Rinaldi-Carmona, M. et al. Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain. Life Sci. 58, 1239–1247 (1996).
Mathews, W. B. et al. Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors. Nucl. Med. Biol. 27, 757–762 (2000).
Bouaboula, M. et al. Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J. Biol. Chem. 270, 13973–13980 (1995).
Bouaboula, M. et al. Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. 312, 637–641 (1995).
Bouaboula, M. et al. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J. Biol. Chem. 272, 22330–22339 (1997).
Compton, D. R., Aceto, M. D., Lowe, J. & Martin, B. R. In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of Δ 9-tetrahydrocannabinol-induced responses and apparent agonist activity. J. Pharmacol. Exp. Ther. 277, 586–594 (1996).
Gueudet, C., Santucci, V., Rinaldi-Carmona, M., Soubrie, P. & Le Fur, G. The CB1 cannabinoid receptor antagonist SR141716A affects A9 dopamine neuronal activity in the rat. Neuroreport 6, 1421–1425 (1995).
Perio, A. et al. Central mediation of the cannabinoid cue: activity of a selective CB1 antagonist, SR141716A. Behav. Pharmacol. 7, 65–71 (1996).
Aceto, M. D., Scates, S. M., Lowe, J. A. & Martin, B. R. Cannabinoid precipitated withdrawal by the selective cannabinoid receptor antagonist, SR141716A. Eur. J. Pharmacol. 282, R1–R2 (1995).
Tsou, K., Patrick, S. L. & Walker, J. M. Physical withdrawal in rats tolerant to Δ 9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. Eur. J. Pharmacol. 280, R13–R15 (1995).
Felder, C. C. et al. LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J. Pharmacol. Exp. Ther. 284, 291–297 (1998).
Meschler, J. P., Kraichely, D. M., Wilken, G. H. & Howlett, A. C. Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) for the CB1 cannabinoid receptor. Biochem. Pharmacol. 60, 1315–1323 (2000).
Cosenza, M. et al. Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281. Synapse 38, 477–482 (2000).
Lan, R. et al. Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand. AAPS Pharm. Sci. 1, E4 (1999).
Pertwee, R. et al. AM630, a competitive cannabinoid receptor antagonist. Life Sci. 56, 1949–1955 (1995).
Rinaldi-Carmona, M. et al. SR144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644–650 (1998).
Cascio, M. G. et al. In vitro and in vivo pharmacological characterization of two novel selective cannabinoid CB2 receptor inverse agonists. Pharmacol. Res. 61, 349–354 (2010).
Miller, A. M. & Stella, N. CB2 receptor-mediated migration of immune cells: it can go either way. Br. J. Pharmacol. 153, 299–308 (2008).
Fernandez-Ruiz, J. et al. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol. Sci. 28, 39–45 (2007).
Wright, K. L., Duncan, M. & Sharkey, K. A. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br. J. Pharmacol. 153, 263–270 (2008).
Lunn, C. A. et al. Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists. Br. J. Pharmacol. 153, 226–239 (2008).
Scheen, A. J. et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368, 1660–1672 (2006).
Nissen, S. E. et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299, 1547–1560 (2008).
Van Gaal, L. F., Rissanen, A. M., Scheen, A. J., Ziegler, O. & Rossner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389–1397 (2005).
Moreira, F. A., Grieb, M. & Lutz, B. Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract. Res. Clin. Endocrinol. Metab. 23, 133–144 (2009).
Nathan, P. J., O'Neill, B. V., Napolitano, A. & Bullmore, E. T. Neuropsychiatric adverse effects of centrally acting antiobesity drugs. CNS Neurosci. Ther. 17, 490–505 (2011).
Di Marzo, V. & Despres, J. P. CB1 antagonists for obesity — what lessons have we learned from rimonabant? Nature Rev. Endocrinol. 5, 633–638 (2009).
Kirilly, E., Gonda, X. & Bagdy, G. CB1 receptor antagonists: new discoveries leading to new perspectives. Acta Physiol. 205, 41–60 (2012).
Tam, J. et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell. Metab. 16, 167–179 (2012).
Lazary, J., Juhasz, G., Hunyady, L. & Bagdy, G. Personalized medicine can pave the way for the safe use of CB1 receptor antagonists. Trends Pharmacol. Sci. 32, 270–280 (2011).
Blankman, J. L. & Cravatt, B. F. Chemical probes of endocannabinoid metabolism. Pharmacol. Rev. 65, 849–871 (2013).
Pertwee, R. G. Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications. Proc. Nutr. Soc. 73, 96–105 (2014).
Pertwee, R. G. The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J. 7, E625–E654 (2005).
Pacher, P. & Kunos, G. Modulating the endocannabinoid system in human health and disease — successes and failures. FEBS J. 280, 1918–1943 (2013).
Pertwee, R. G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br. J. Pharmacol. 153, 199–215 (2008).
Pertwee, R. G. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem. 17, 1360–1381 (2010).
Pertwee, R. G. & Cascio, M. G. in Handbook of Cannabis (ed. Pertwee, R. G.) 115–136 (Oxford University Press, 2014).
Pertwee, R. G. Pharmacology of cannabinoid receptor ligands. Curr. Med. Chem. 6, 635–664 (1999).
McHugh, D., Page, J., Dunn, E. & Bradshaw, H. B. Δ9-Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br. J. Pharmacol. 165, 2414–2424 (2012).
De Petrocellis, L. et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 163, 1479–1494 (2011).
Di Marzo, V. A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the work of British scientists. Trends Pharmacol. Sci. 27, 134–140 (2006).
Howlett, A. C., Blume, L. C. & Dalton, G. D. CB1 cannabinoid receptors and their associated proteins. Curr. Med. Chem. 17, 1382–1393 (2010).
Smith, T. H., Sim-Selley, L. J. & Selley, D. E. Cannabinoid CB1 receptor-interacting proteins: novel targets for central nervous system drug discovery? Br. J. Pharmacol. 160, 454–466 (2010).
Tan, B. et al. Targeted lipidomics: discovery of new fatty acyl amides. AAPS J. 8, E461–E465 (2006).
Tan, B. et al. Identification of endogenous acyl amino acids based on a targeted lipidomics approach. J. Lipid Res. 51, 112–119 (2010).
Milman, G. et al. N-Arachidonoyl l-serine, a novel endocannabinoid-like brain constituent with vasodilatory properties. Proc. Natl Acad. Sci. USA 103, 2428–2433 (2006).
Cohen-Yeshurun, A. et al. N-Arachidonoyl-l-serine is neuroprotective after traumatic brain injury by reducing apoptosis. J. Cereb. Blood Flow Metab. 31, 1768–1777 (2011).
Cohen-Yeshurun, A. et al. N-arachidonoyl-l-serine (AraS) possesses pro-neurogenic properties in vitro and in vivo following traumatic brain injury. J. Cereb. Blood Flow Metab. 33, 1242–1250 (2013).
Pucci, M. et al. Epigenetic control of skin differentiation genes by phytocannabinoids. Br. J. Pharmacol. 170, 581–591 (2013).
Pasquariello, N., Oddi, S., Malaponti, M. & Maccarrone, M. Regulation of gene transcription and keratinocyte differentiation by anandamide. Vitam. Horm. 81, 441–467 (2009).
Leweke, F. M. et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2, e94 (2012).
Porter, B. E. & Jacobson, C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 29, 574–577 (2013).
Cunha, J. M. et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacol. 21, 175–185 (1980).
Wood, T. B., Spivey, W. T. N. & Easterfield, T. H. Cannabinol. Part I. J. Chem. Soc. 75, 20–36 (1899).
Cahn, R. S. Cannabis indica resin, Part, III The constitution of Cannabinol. J. Chem. Soc. 1342–1353 (1932).
Mechoulam, R. & Shvo, Y. The structure of cannabidiol. Tetrahedron 19, 2073–2078 (1963).
Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).
Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996).
Zygmunt, P. M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457 (1999).
Smart, D. et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol. 129, 227–230 (2000).
Piomelli, D. A fatty gut feeling. Trends Endocrinol. Metab. 24, 332–341 (2013).
Bandiera, T., Ponzano, S. & Piomelli, D. Advances in the discovery of N-acylethanolamine acid amidase inhibitors. Pharmacol. Res. 86C, 11–17 (2014).
Schlosburg, J. E. et al. Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice. J. Pharmacol. Exp. Ther. 350, 196–204 (2014).
Galve-Roperh, I. et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog. Lipid Res. 52, 633–650 (2013).
Katona, I. & Freund, T. F. Multiple functions of endocannabinoid signaling in the brain. Annu. Rev. Neurosci. 35, 529–558 (2012).
Piomelli, D. & Sasso, O. Peripheral gating of pain signals by endogenous lipid mediators. Nature Neurosci. 17, 164–174 (2014).
Syed, Y. Y., McKeage, K. & Scott, L. J. Δ-9-tetrahydrocannabinol/cannabidiol (Sativex): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs 74, 563–578 (2014).
Roitman, P., Mechoulam, R., Cooper-Kazaz, R. & Shalev, A. Preliminary, open-label, pilot study of add-on oral δ(9)-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin. Drug Investig. 34, 587–591 (2014).
Bisogno, T. et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol. 163, 463–468 (2003).
Research in the laboratory of R.M. was supported by the Kessler Family Foundation, Boston, USA, and by a grant from US National Institute on Drug Abuse (NIDA), DA-9789. The research of R.P. was supported by NIDA grants DA-3934, DA-9789 and DA-3672 and GW Pharmaceuticals and the research of A.H. was supported by NIDA grant DA-3690.
The authors declare no competing financial interests.
The potency with which a compound binds to a particular receptor; the higher the affinity of the compound, the lower the concentration at which it achieves a given level of receptor occupancy.
Compounds that can activate pharmacological receptors; a full agonist is more potent than a partial agonist and so usually produces a greater maximum functional response.
- Allosteric modulators
Drugs that can act on an allosteric site of a receptor to increase or to reduce the ability of an agonist or an inverse agonist to induce a functional response when it targets a different (orthosteric) site on the same receptor.
A compound that can bind to, but cannot activate, a receptor by targeting its orthosteric site and that can therefore prevent both drug-induced agonism and drug-induced inverse agonism at this receptor.
Another term for pain relief.
A process of programmed cell death that usually has advantageous consequences.
A condition that is characterized by immobility and muscular rigidity.
An endogenous compound that can directly activate or block cannabinoid CB1 and/or CB2 or that can act as a positive or negative allosteric modulator to increase or to reduce responses of CB1 and/or CB2 to direct agonists or inverse agonists.
- G protein-coupled receptor
(GPCR). A seven-transmembrane domain receptor that induces G-protein-mediated activation of intracellular signal transduction pathways when occupied by an agonist.
A cannabis-derived preparation that consists mostly of dried cannabis resin.
A condition that is characterized by decreased bodily movement.
- Inverse agonist
A compound that binds to a receptor in a manner that induces a pharmacological response opposite to the response that is induced by an agonist for the same receptor.
- Relative intrinsic activity
The relative ability of drug–receptor complexes to produce maximum functional responses; a high-efficacy agonist needs to occupy fewer receptors to produce a maximal response than a low-efficacy agonist (also known as a partial agonist).
- Retrograde synaptic messengers
Compounds that are released by a postsynaptic dendrite or cell body, but that act presynaptically — for example, to influence the release of a transmitter.
- Structure–activity relationship
(SAR). The relationship between the pharmacological activity of compounds and their chemical structures.
- Transient receptor potential cation channel subfamily V member 1
(TRPV1). A member of a superfamily of transmembrane cation channels; it was previously known as vanilloid receptor 1.
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Mechoulam, R., Hanuš, L., Pertwee, R. et al. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 15, 757–764 (2014). https://doi.org/10.1038/nrn3811
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