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Roger G. Pertwee - One of the best experts on this subject based on the ideXlab platform.
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emerging strategies for exploiting Cannabinoid Receptor agonists as medicines
British Journal of Pharmacology, 2009Co-Authors: Roger G. PertweeAbstract:Medicines that activate Cannabinoid CB(1) and CB(2) Receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for Cannabinoid Receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a Cannabinoid Receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting Cannabinoid Receptors located outside the blood-brain barrier; (ii) targeting Cannabinoid Receptors expressed by a particular tissue; (iii) targeting up-regulated Cannabinoid Receptors; (iv) targeting Cannabinoid CB(2) Receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.
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pharmacology of Cannabinoid Receptor ligands
Current Medicinal Chemistry, 1999Co-Authors: Roger G. PertweeAbstract:Mammalian tissues contain at least two types of Cannabinoid Receptor, CB 1 and CB 2 , both coupled to G proteins. CB 1 Receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB 2 Receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for Cannabinoid Receptors has also been demonstrated. The discovery of this 'endogenous Cannabinoid system' has been paralleled by a renewed interest in possible therapeutic applications of Cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel Cannabinoid Receptor ligands, including several that show marked selectivity for CB 1 or CB 2 Receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB 1 and CB 2 Receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of Cannabinoid Receptor agonists, as determined using cyclic AMP or [ 35 S]GTPγS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB 1 or CB 2 Receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by Cannabinoid Receptor agonists and the possibility that the ligands producing such 'inverse cannabimimetic effects' are inverse agonists rather than pure antagonists is discussed.
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structure activity relationships of pyrazole derivatives as Cannabinoid Receptor antagonists
Journal of Medicinal Chemistry, 1999Co-Authors: Ruoxi Lan, Roger G. Pertwee, Susanthi R. Fernando, Qian Liu, Pusheng Fan, Sonyuan Lin, Deirdre S Mccallion, Alexandros MakriyannisAbstract:As a potent, specific antagonist for the brain Cannabinoid Receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compound for initiating studies designed to examine the structure-activity relationships of related compounds and to search for more selective and potent cannabimimetic ligands. A series of pyrazole derivatives was designed and synthesized to aid in the characterization of the Cannabinoid Receptor binding sites and also to serve as potentially useful pharmacological probes. Therapeutically, such compounds may have the ability to antagonize harmful side effects of Cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain Cannabinoid CB1 Receptor antagonistic activity included (a) a para-substituted phenyl ring at the 5-position, (b) a carboxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this series contained a p-iodophenyl group at the 5-position, a piperidinyl carboxamide at the 3-position, and a 2,4-dichlorophenyl group at the 1-position of the pyrazole ring. The iodinated nature of this compound offers additional utility as a gamma-enriching SPECT (single photon emission computed tomography) ligand that may be useful in characterizing brain CB1 Receptor binding in vivo.
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pharmacological characterization of three novel Cannabinoid Receptor agonists in the mouse isolated vas deferens
European Journal of Pharmacology, 1995Co-Authors: Roger G. Pertwee, Graeme Griffin, Julia A H Lainton, John W HuffmanAbstract:The novel compounds, 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole, produced a dose-related inhibition of electrically evoked contractions of the mouse vas deferens, with IC50 values of 2.56 nM, 3.38 nM and 639 nM respectively. Kd values of the selective CB1 Cannabinoid Receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloridel, determined in the vas deferens from experiments with these compounds are 1.34 nM, 3.86 nM and 8.06 nM respectively, indicating their susceptibility to antagonism by SR141716A is similar to that of their parent compound, the CB1 Cannabinoid Receptor agonist WIN 55,212-2 {(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone}. SR141716A (100 nM) had no effect on the actions of two non-Cannabinoid Receptor agonists, morphine and clonidine. These results provide strong support for the hypothesis that 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole are Cannabinoid Receptor agonists and confirm that the WIN 55,212-2 molecule can be modified considerably without detectable loss of Cannabinoid activity.
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am630 a competitive Cannabinoid Receptor antagonist
Life Sciences, 1995Co-Authors: Roger G. Pertwee, Graeme Griffin, Susanthi R. Fernando, Adam P. Hill, Alexandros MakriyannisAbstract:AM630 (iodopravadoline), a novel aminoalkylindole, has been found to attenuate the ability of a number of Cannabinoids to inhibit electrically-evoked twitches of the mouse isolated vas deferens. It did not block the inhibitory effects of morphine or clonidine on the twitch response. AM630 behaved as a competitive antagonist of CP 55,940, WIN 55,212-2, anandamide and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (AM356), producing rightward shifts in the log concentration response curves of these Cannabinoid Receptor agonists that were concentration-dependent, essentially parallel and not accompanied by any decrease in the size of maximal response. AM630 also produced concentration-dependent, parallel rightward shifts in the log concentration-response curve of delta 9-THC. However, these shifts were accompanied by a decrease in the maximal response. AM630 was markedly more potent as an antagonist of delta 9-THC and CP 55,940 (Kd = 14.0 and 17.3 nM respectively) than as an antagonist of WIN 55,212-2, AM356 or anandamide (Kd = 36.5, 85.9 and 278.8 nM respectively). These differences in dissociation constant imply that the mouse vas deferens may contain more than one type of Cannabinoid Receptor. The data also indicate that the Receptors for which AM630 has the highest affinity may not be CB1 Cannabinoid Receptors as the CB1 selective antagonist, SR141716A, is known to be equally potent in attenuating the inhibitory effects of CP 55,940 and anandamide on the twitch response of the mouse vas deferens.
Didier M Lambert - One of the best experts on this subject based on the ideXlab platform.
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synthesis and activity of 1 3 5 triphenylimidazolidine 2 4 diones and 1 3 5 triphenyl 2 thioxoimidazolidin 4 ones characterization of new cb1 Cannabinoid Receptor inverse agonists antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Giulio G Muccioli, Johan Wouters, Jacques Poupaert, Wolfgang Poppitz, Gerhard K E Scriba, Caroline Charlier, Teresa Pizza, Pierluigi Di Pace, Paolo De Martino, Didier M LambertAbstract:Obesity and metabolic syndrome, along with drug dependence (nicotine, alcohol, opiates), are two of the major therapeutic applications for CB(1) Cannabinoid Receptor antagonists and inverse agonists. In the present study, we report the synthesis and structure-affinity relationships of 1,5-diphenylimidazolidine-2,4-dione and 1,3,5-triphenylimidazolidine-2,4-dione derivatives. These new 1,3,5-triphenylimidazolidine-2,4-dione derivatives and their thio isosteres were obtained by an original pathway and exhibited interesting affinity and selectivity for the human CB(1) Cannabinoid Receptor. A [(35)S]-GTPgammaS binding assay revealed the inverse agonist properties of the compounds at the CB(1) Cannabinoid Receptor. Furthermore, molecular modeling studies were conducted in order to delineate the binding mode of this series of derivatives into the CB(1) Cannabinoid Receptor. 1,3-Bis(4-bromophenyl)-5-phenylimidazolidine-2,4-dione (25) and 1,3-bis(4-chlorophenyl)-5-phenylimidazolidine-2,4-dione (23) are the imidazolidine-2,4-dione derivatives possessing the highest affinity for the human CB(1) Cannabinoid Receptor reported to date.
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1 benzhydryl 3 phenylurea and 1 benzhydryl 3 phenylthiourea derivatives new templates among the cb1 Cannabinoid Receptor inverse agonists
Journal of Medicinal Chemistry, 2005Co-Authors: Giulio G Muccioli, Johan Wouters, Jacques Poupaert, Wolfgang Poppitz, Gerhard K E Scriba, Didier M LambertAbstract:New 1-benzhydryl-3-phenylurea derivatives and their 1-benzhydryl-3-phenylthiourea isosteres were synthesized and evaluated for their human CB1 and CB2 Cannabinoid Receptor affinity. These compounds proved to be selective CB1 Cannabinoid Receptor ligands, acting as inverse agonists in a [35S]-GTPgammaS assay. The affinity of 3,5,5'-triphenylimidazolidine-2,4-dione and 3,5,5'-triphenyl-2-thioxoimidazolidin-4-one derivatives, possessing the 1-benzhydryl-3-phenylurea and 1-benzhydryl-3-phenylthiourea moiety, respectively, was also evaluated. In conclusion, the 1-benzhydryl-3-phenylurea scaffold seems to be a new interesting template of CB1 Cannabinoid Receptor inverse agonists.
Giulio G Muccioli - One of the best experts on this subject based on the ideXlab platform.
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synthesis and activity of 1 3 5 triphenylimidazolidine 2 4 diones and 1 3 5 triphenyl 2 thioxoimidazolidin 4 ones characterization of new cb1 Cannabinoid Receptor inverse agonists antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Giulio G Muccioli, Johan Wouters, Jacques Poupaert, Wolfgang Poppitz, Gerhard K E Scriba, Caroline Charlier, Teresa Pizza, Pierluigi Di Pace, Paolo De Martino, Didier M LambertAbstract:Obesity and metabolic syndrome, along with drug dependence (nicotine, alcohol, opiates), are two of the major therapeutic applications for CB(1) Cannabinoid Receptor antagonists and inverse agonists. In the present study, we report the synthesis and structure-affinity relationships of 1,5-diphenylimidazolidine-2,4-dione and 1,3,5-triphenylimidazolidine-2,4-dione derivatives. These new 1,3,5-triphenylimidazolidine-2,4-dione derivatives and their thio isosteres were obtained by an original pathway and exhibited interesting affinity and selectivity for the human CB(1) Cannabinoid Receptor. A [(35)S]-GTPgammaS binding assay revealed the inverse agonist properties of the compounds at the CB(1) Cannabinoid Receptor. Furthermore, molecular modeling studies were conducted in order to delineate the binding mode of this series of derivatives into the CB(1) Cannabinoid Receptor. 1,3-Bis(4-bromophenyl)-5-phenylimidazolidine-2,4-dione (25) and 1,3-bis(4-chlorophenyl)-5-phenylimidazolidine-2,4-dione (23) are the imidazolidine-2,4-dione derivatives possessing the highest affinity for the human CB(1) Cannabinoid Receptor reported to date.
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1 benzhydryl 3 phenylurea and 1 benzhydryl 3 phenylthiourea derivatives new templates among the cb1 Cannabinoid Receptor inverse agonists
Journal of Medicinal Chemistry, 2005Co-Authors: Giulio G Muccioli, Johan Wouters, Jacques Poupaert, Wolfgang Poppitz, Gerhard K E Scriba, Didier M LambertAbstract:New 1-benzhydryl-3-phenylurea derivatives and their 1-benzhydryl-3-phenylthiourea isosteres were synthesized and evaluated for their human CB1 and CB2 Cannabinoid Receptor affinity. These compounds proved to be selective CB1 Cannabinoid Receptor ligands, acting as inverse agonists in a [35S]-GTPgammaS assay. The affinity of 3,5,5'-triphenylimidazolidine-2,4-dione and 3,5,5'-triphenyl-2-thioxoimidazolidin-4-one derivatives, possessing the 1-benzhydryl-3-phenylurea and 1-benzhydryl-3-phenylthiourea moiety, respectively, was also evaluated. In conclusion, the 1-benzhydryl-3-phenylurea scaffold seems to be a new interesting template of CB1 Cannabinoid Receptor inverse agonists.
Ken Mackie - One of the best experts on this subject based on the ideXlab platform.
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gpr55 is a Cannabinoid Receptor that increases intracellular calcium and inhibits m current
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jane E Lauckner, Huei Ying Chen, Huichen Lu, Jill B Jensen, Bertil Hille, Ken MackieAbstract:The CB1 Cannabinoid Receptor mediates many of the psychoactive effects of Δ9THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB1/CB2 Receptors may contribute to the behavioral, vascular, and immunological actions of Δ9THC and endogenous Cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled Receptor, is a Cannabinoid Receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various Cannabinoids (Δ9THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve Gq, G12, RhoA, actin, phospholipase C, and calcium release from IP3R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a Cannabinoid Receptor with signaling distinct from CB1 and CB2.
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gpr55 is a Cannabinoid Receptor that increases intracellular calcium and inhibits m current
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Jane E Lauckner, Huei Ying Chen, Huichen Lu, Jill B Jensen, Bertil Hille, Ken MackieAbstract:The CB1 Cannabinoid Receptor mediates many of the psychoactive effects of Δ9THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB1/CB2 Receptors may contribute to the behavioral, vascular, and immunological actions of Δ9THC and endogenous Cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled Receptor, is a Cannabinoid Receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various Cannabinoids (Δ9THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve Gq, G12, RhoA, actin, phospholipase C, and calcium release from IP3R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a Cannabinoid Receptor with signaling distinct from CB1 and CB2.
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a light and electron microscopic study of the cb1 Cannabinoid Receptor in the primate spinal cord
Journal of Neurocytology, 1999Co-Authors: Weiyi Ong, Ken MackieAbstract:The distribution of Cannabinoid Receptors was studied in the monkey spinal cord by immunocytochemistry and electron microscopy, using an antibody to the CB1 brain Cannabinoid Receptor. Large numbers of labelled neurons were observed in all portions of the grey matter of the spinal cord. These included small diameter 9–16µm neurons in the dorsal horn, larger (40–60µm) neurons in the intermediate grey, and very large (60–100µm), motor neurons in the ventral horn. Reaction product was observed in dendrites postsynaptic to unlabelled axon terminals. Since Cannabinoid Receptor activation decreases neuronal excitability by several mechanisms, including inhibition of voltage dependent calcium channels, the dense staining of CB1 in dorsal horn neurons suggests that CB1 could reduce calcium influx through such channels in these neurons. This, in turn, could decrease calcium-dependent changes in synaptic transmission and decrease sensitisation to nociceptive stimuli in these neurons. Similarly, the dense staining of CB1 in ventral horn cells suggests that Cannabinoid Receptors could limit calcium influx through voltage dependent calcium channels in these neurons, and could be significant in terms of neuroprotection to these neurons.
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anandamide an endogenous cannabimimetic eicosanoid binds to the cloned human Cannabinoid Receptor and stimulates Receptor mediated signal transduction
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Christian C Felder, Ken Mackie, Eileen M Briley, Julius Axelrod, John T Simpson, William A. DevaneAbstract:Arachidonylethanolamide (anandamide), a candidate endogenous Cannabinoid ligand, has recently been isolated from porcine brain and displayed Cannabinoid-like binding activity to synaptosomal membrane preparations and mimicked Cannabinoid-induced inhibition of the twitch response in isolated murine vas deferens. In this study, anandamide and several congeners were evaluated as Cannabinoid agonists by examining their ability to bind to the cloned Cannabinoid Receptor, inhibit forskolin-stimulated cAMP accumulation, inhibit N-type calcium channels, and stimulate one or more functional second messenger responses. Synthetic anandamide, and all but one congener, competed for [3H]CP55,940 binding to plasma membranes prepared from L cells expressing the rat Cannabinoid Receptor. The ability of anandamide to activate Receptor-mediated signal transduction was evaluated in Chinese hamster ovary (CHO) cells expressing the human Cannabinoid Receptor (HCR, termed CHO-HCR cells) and compared to control CHO cells expressing the muscarinic m5 Receptor (CHOm5 cells). Anandamide inhibited forskolin-stimulated cAMP accumulation in CHO-HCR cells, but not in CHOm5 cells, and this response was blocked with pertussis toxin. N-type calcium channels were inhibited by anandamide and several active congeners in N18 neuroblastoma cells. Anandamide stimulated arachidonic acid and intracellular calcium release in both CHOm5 and CHO-HCR cells and had no effect on the release of inositol phosphates or phosphatidylethanol, generated after activation of phospholipase C and D, respectively. Anandamide appears to exhibit the essential criteria required to be classified as a Cannabinoid/anandamide Receptor agonist and shares similar nonReceptor effects on arachidonic acid and intracellular calcium release as other Cannabinoid agonists.
Martin Lotz - One of the best experts on this subject based on the ideXlab platform.
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anadamide an endogenous Cannabinoid Receptor agonist inhibits lymphocyte proliferation and induces apoptosis
Journal of Neuroimmunology, 1994Co-Authors: Herbert Schwarz, Francisco J Blanco, Martin LotzAbstract:Abstract This study examined the immunoregulatory effects of anadamide, the recently identified first endogenous Cannabinoid Receptor ligand. Anadamide caused dose-dependent inhibition of mitogen-induced T and B lymphocyte proliferation. Its potency was 3- and 10-fold less than that of the synthetic Cannabinoids Δ 8 -tetrahydrocannabinol ( Δ 8 -THC) and CP55940, respectively. Anadamide effects on DNA synthesis in T and B lymphocytes occured rapidly as exposure of the cells during the final 4 h of culture was sufficient to achieve > 40% inhibition. Low doses of anadamide which caused significant inhibition of lymphocyte proliferation caused DNA fragmentation as demonstrated by immunohistochemistry, FACS analysis and Southern blotting. Apoptosis was also induced by high concentrations of Δ 8 -THC, but not by CP55940. Brain and peripheral Cannabinoid Receptor mRNA was expressed in PBMC with varying levels between individual donors. In summary, these findings demonstrate immunosuppressive effects of anadamide which are associated with inhibition of lymphocyte proliferation and the induction of cell death by apoptosis.
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anadamide an endogenous Cannabinoid Receptor agonist inhibits lymphocyte proliferation and induces apoptosis
Journal of Neuroimmunology, 1994Co-Authors: Herbert Schwarz, F Blanco, Martin LotzAbstract:This study examined the immunoregulatory effects of anadamide, the recently identified first endogenous Cannabinoid Receptor ligand. Anadamide caused dose-dependent inhibition of mitogen-induced T and B lymphocyte proliferation. Its potency was 3- and 10-fold less than that of the synthetic Cannabinoids delta 8-tetrahydrocannabinol (delta 8-THC) and CP55940, respectively. Anadamide effects on DNA synthesis in T and B lymphocytes occurred rapidly as exposure of the cells during the final 4 h of culture was sufficient to achieve > 40% inhibition. Low doses of anadamide which caused significant inhibition of lymphocyte proliferation caused DNA fragmentation as demonstrated by immunohistochemistry, FACS analysis and Southern blotting. Apoptosis was also induced by high concentrations of delta 8-THC, but not by CP55940. Brain and peripheral Cannabinoid Receptor mRNA was expressed in PBMC with varying levels between individual donors. In summary, these findings demonstrate immunosuppressive effects of anadamide which are associated with inhibition of lymphocyte proliferation and the induction of cell death by apoptosis.
