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Ferdinando Nicoletti - One of the best experts on this subject based on the ideXlab platform.
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wag rij rats show a reduced expression of CB1 Receptors in thalamic nuclei and respond to the CB1 Receptor agonist r win55 212 2 with a reduced incidence of spike wave discharges
Epilepsia, 2010Co-Authors: Clementina M. Van Rijn, Ines Santolini, Aleksandra Gabova, Masashiko Watanabe, Aleksandra Badura, Gilles Van Luijtelaar, Vincenzo Cuomo, Silvana Gaetani, Jin Fu, Ferdinando NicolettiAbstract:Purpose: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) Receptors. Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of “presymptomatic” 2-month old and “symptomatic” 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 Receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB1 Receptor agonist, R(+)WIN55,212-2 (3–12 mg/kg, s.c.), given alone or combined with the CB1 Receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.). Results: Data showed a reduction of CB1 Receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB1 Receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB1 Receptor Agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 Receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 Receptors are targeted by novel antiabsence drugs.
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WAG/Rij rats show a reduced expression of CB1 Receptors in thalamic nuclei and respond to the CB1 Receptor agonist, R(+)WIN55,212-2, with a reduced incidence of spike-wave discharges
Epilepsia, 2010Co-Authors: Clementina M. Van Rijn, Ines Santolini, Aleksandra Gabova, Masashiko Watanabe, Aleksandra Badura, Gilles Van Luijtelaar, Vincenzo Cuomo, Silvana Gaetani, Jin Fu, Ferdinando NicolettiAbstract:Purpose: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) Receptors. Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of “presymptomatic” 2-month old and “symptomatic” 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 Receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB1 Receptor agonist, R(+)WIN55,212-2 (3–12 mg/kg, s.c.), given alone or combined with the CB1 Receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.). Results: Data showed a reduction of CB1 Receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB1 Receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB1 Receptor Agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 Receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 Receptors are targeted by novel antiabsence drugs.
Fiona Jeremiah - One of the best experts on this subject based on the ideXlab platform.
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Low brain penetrant CB1 Receptor Agonists for the treatment of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Julia M. Adam, Fiona Jeremiah, Takao Kiyoi, John K. Clark, Keneth Davies, Ruth Fields, Stuart Francis, Kathryn Everett, Maurice S. Maidment, Angus J. MorrisonAbstract:Novel, low brain penetrant, orally bioavailable CB1 Receptor Agonists were designed starting from a mature lead series of potent brain penetrant CB1 Receptor Agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 Receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
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Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 Receptor Agonists.
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Takao Kiyoi, Julia M. Adam, Darren Edwards, John K. Clark, Keneth Davies, Alexandra M Easson, Helen Feilden, Ruth Fields, Stuart Francis, Fiona JeremiahAbstract:Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid Receptor Agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 Receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
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Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 Receptor Agonists.
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Elizabeth M. Moir, Jim Cairns, Phillip Cowley, Fiona Jeremiah, Takao Kiyoi, Kazuya Yoshiizumi, Richard Morphy, Jason Tierney, Morag Ferguson, Grant WishartAbstract:Abstract Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 Receptor Agonists. The CB1 Receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
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Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 Receptor Agonists
MedChemComm, 2010Co-Authors: Julia M. Adam, Jim Cairns, Wilson Caulfield, Phillip Cowley, Iain Cumming, Morag Easson, Darren Edwards, Richard Goodwin, Morag Ferguson, Fiona JeremiahAbstract:A novel CB1 Receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water solubility. Structural variations were explored with the aim of introducing water solubility and improving potency. This led to the discovery of Org 28611, a potent, water soluble CB1 Receptor agonist, which was selected for clinical evaluation as a potential intravenous analgesic agent.
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design synthesis and structure activity relationships of indole 3 carboxamides as novel water soluble cannabinoid CB1 Receptor Agonists
MedChemComm, 2010Co-Authors: Julia M. Adam, Jim Cairns, Wilson Caulfield, Iain Cumming, Morag Easson, Darren Edwards, Richard Goodwin, Morag Ferguson, Phillip M Cowley, Fiona JeremiahAbstract:A novel CB1 Receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water solubility. Structural variations were explored with the aim of introducing water solubility and improving potency. This led to the discovery of Org 28611, a potent, water soluble CB1 Receptor agonist, which was selected for clinical evaluation as a potential intravenous analgesic agent.
Clementina M. Van Rijn - One of the best experts on this subject based on the ideXlab platform.
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wag rij rats show a reduced expression of CB1 Receptors in thalamic nuclei and respond to the CB1 Receptor agonist r win55 212 2 with a reduced incidence of spike wave discharges
Epilepsia, 2010Co-Authors: Clementina M. Van Rijn, Ines Santolini, Aleksandra Gabova, Masashiko Watanabe, Aleksandra Badura, Gilles Van Luijtelaar, Vincenzo Cuomo, Silvana Gaetani, Jin Fu, Ferdinando NicolettiAbstract:Purpose: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) Receptors. Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of “presymptomatic” 2-month old and “symptomatic” 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 Receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB1 Receptor agonist, R(+)WIN55,212-2 (3–12 mg/kg, s.c.), given alone or combined with the CB1 Receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.). Results: Data showed a reduction of CB1 Receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB1 Receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB1 Receptor Agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 Receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 Receptors are targeted by novel antiabsence drugs.
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WAG/Rij rats show a reduced expression of CB1 Receptors in thalamic nuclei and respond to the CB1 Receptor agonist, R(+)WIN55,212-2, with a reduced incidence of spike-wave discharges
Epilepsia, 2010Co-Authors: Clementina M. Van Rijn, Ines Santolini, Aleksandra Gabova, Masashiko Watanabe, Aleksandra Badura, Gilles Van Luijtelaar, Vincenzo Cuomo, Silvana Gaetani, Jin Fu, Ferdinando NicolettiAbstract:Purpose: Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) Receptors. Methods: Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of “presymptomatic” 2-month old and “symptomatic” 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 Receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB1 Receptor agonist, R(+)WIN55,212-2 (3–12 mg/kg, s.c.), given alone or combined with the CB1 Receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.). Results: Data showed a reduction of CB1 Receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB1 Receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB1 Receptor Agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion: These data indicate that the development of absence seizures is associated with plastic modifications of CB1 Receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 Receptors are targeted by novel antiabsence drugs.
Julia M. Adam - One of the best experts on this subject based on the ideXlab platform.
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Low Brain Penetrant CB1 Receptor Agonists for the Treatment of Neuropathic Pain.
ChemInform, 2012Co-Authors: Julia M. AdamAbstract:Among a variety of indolyl-oxadiazole and -thiadiazole derivatives, compound (Ia) is identified as an orally bioavailable, low brain penetrant CB1 Receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which is selected for clinical development.
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Low brain penetrant CB1 Receptor Agonists for the treatment of neuropathic pain.
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Julia M. Adam, Fiona Jeremiah, Takao Kiyoi, John K. Clark, Keneth Davies, Ruth Fields, Stuart Francis, Kathryn Everett, Maurice S. Maidment, Angus J. MorrisonAbstract:Novel, low brain penetrant, orally bioavailable CB1 Receptor Agonists were designed starting from a mature lead series of potent brain penetrant CB1 Receptor Agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 Receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
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design synthesis and structure activity relationships of indo 3 yl heterocyclic derivatives as Agonists of the CB1 Receptor discovery of a clinical candidate
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Paul Ratcliffe, Julia M. Adam, John K. Clark, Alexandra M Easson, James Baker, Roberta Bursi, Robert A. Campbell, Jean E. Cottney, Maureen Deehan, Daniel EckerAbstract:We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 Receptor Agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.
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Design, synthesis and structure–activity relationships of (indo-3-yl) heterocyclic derivatives as Agonists of the CB1 Receptor. Discovery of a clinical candidate
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Paul Ratcliffe, Julia M. Adam, John K. Clark, Alexandra M Easson, James Baker, Roberta Bursi, Robert A. Campbell, Jean E. Cottney, Maureen Deehan, Daniel EckerAbstract:Abstract We report an expansion of the structure–activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 Receptor Agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.
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Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 Receptor Agonists.
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Takao Kiyoi, Julia M. Adam, Darren Edwards, John K. Clark, Keneth Davies, Alexandra M Easson, Helen Feilden, Ruth Fields, Stuart Francis, Fiona JeremiahAbstract:Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid Receptor Agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 Receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
Roger G. Pertwee - One of the best experts on this subject based on the ideXlab platform.
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cannabidiol antagonizes cannabinoid Receptor Agonists and noradrenaline in the mouse vas deferens
European Journal of Pharmacology, 2002Co-Authors: Roger G. Pertwee, Ruth A Ross, Susan J Craib, Adèle ThomasAbstract:Abstract The nonpsychoactive plant cannabinoid, (−)-cannabidiol, modulates in vivo responses to Δ9-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB1 Receptor Agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB1 Receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316–10 μM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a KB value (120.3 nM) well below its reported cannabinoid Receptor CB1/CB2 Ki values. Cannabidiol (10 μM) also antagonized (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; KB=34 nM) and [ d -Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO; KB=5.6 μM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to β, γ-methyleneadenosine 5′-triphosphate. At 3.16–10 μM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB1 or CB2 Receptors.
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structure activity relationship for the endogenous cannabinoid anandamide and certain of its analogues at vanilloid Receptors in transfected cells and vas deferens
British Journal of Pharmacology, 2001Co-Authors: Ruth A Ross, Susan J Craib, Michael T Gibson, Heather C Brockie, Mark Leslie, Ghazaleh Pashmi, Vincenzo Di Marzo, Roger G. PertweeAbstract:This study was directed at exploring the structure-activity relationship for anandamide and certain of its analogues at the rat VR1 Receptor in transfected cells and at investigating the relative extent to which anandamide interacts with CB1 and vanilloid Receptors in the mouse vas deferens. pKi values for displacement of [3H]-resiniferatoxin from membranes of rVR1 transfected CHO cells were significantly less for anandamide (5.78) than for its structural analogues N-(4-hydroxyphenyl)-arachidonylamide (AM404; 6.18) and N-(3-methoxy-4-hydroxy)benzyl-arachidonylamide (arvanil; 6.77). pEC50 values for stimulating 45Ca2+ uptake into rVR1 transfected CHO cells were significantly less for anandamide (5.80) than for AM404 (6.32) or arvanil (9.29). Arvanil was also significantly more potent than capsaicin (pEC50=7.37), a compound with the same substituted benzyl polar head group as arvanil. In the mouse vas deferens, resiniferatoxin was 218 times more potent than capsaicin as an inhibitor of electrically-evoked contractions. Both drugs were antagonized to a similar extent by capsazepine (pKB=6.93 and 7.18 respectively) but were not antagonized by SR141716A (1 μM). Anandamide was less susceptible than capsaicin to antagonism by capsazepine (pKB=6.02) and less susceptible to antagonism by SR141716A (pKB=8.66) than methanandamide (pKB=9.56). WIN55212 was antagonized by SR141716A (pKB=9.02) but not by capsazepine (10 μM). In conclusion, anandamide and certain of its analogues have affinity and efficacy at the rat VR1 Receptor. In the mouse vas deferens, which seems to express vanilloid and CB1 Receptors, both Receptor types appear to contribute to anandamide-induced inhibition of evoked contractions. Keywords: Anandamide, vanilloid, cannabinoid, VR1 transfected cells, structure-activity, mouse vas deferens, AM404, arvanil, capsaicin, RTX Introduction There is mounting evidence that the endogenous cannabinoid, anandamide (Figure 1), can serve as an agonist at the vanilloid VR1 Receptor as well as at cannabinoid Receptors (Pertwee, 1999; 2000; 2001; Zygmunt et al., 1999; Smart et al., 2000). Thus, this fatty acid amide has been shown to mediate vasodilation that is inhibited by the vanilloid Receptor antagonist, capsazepine, but not by the CB1-selective antagonist, SR141716A, and patch-clamp experiments in transfected cells have demonstrated that anandamide is an agonist at both rat and human VR1 Receptors (Zygmunt et al., 1999; Smart et al., 2000). Certain analogues of anandamide have also been reported to activate vanilloid as well as cannabinoid Receptors and experiments with these compounds suggest that the structural requirements for interaction with VR1 and CB1 Receptors are quite different (Melck et al., 1999; Zygmunt et al., 1999; Smart et al., 2000). For example, it has been shown that methanandamide (Figure 1), which is more potent than anandamide as a CB1 Receptor agonist (Pertwee, 1999; 2000), is considerably less potent than anandamide as a VR1 Receptor agonist (Zygmunt et al., 1999; Smart et al., 2000). In addition, there is evidence that the anandamide uptake inhibitor, AM404 (Figure 1), activates rat VR1 Receptors at concentrations lower than those at which it binds to CB1 Receptors (Pertwee, 2000; 2001; Jerman et al., 2000; Zygmunt et al., 2000). On the other hand, non-eicosanoid CB1 Receptor Agonists such as CP55940 and (+)-WIN55212 do not appear to activate vanilloid VR1 Receptors (Zygmunt et al., 1999; Smart et al., 2000). Figure 1 Structures of anandamide (arachidonyl ethanolamide), methanandamide, AEA (22 : 4, n-6) (docosatetraenyl ethanolamide), AEA (18 : 2, n-6) (linoleyl ethanolamide), MAFP (methyl arachidonyl fluorophosphonate), AM404 (4-hydroxyphenyl ... In this study we have used both radioligand binding and 45Ca2+ uptake assays to investigate the structural features of anandamide and of certain of its analogues that determine affinity and/or potency at rat VR1 Receptors stably transfected into CHO cells. Included in this study are the endogenous ethanolamides: anandamide (22 : 4, n-6) (AEA 22 : 4); palmitylethanolamide (PEA), and mead acid ethanolamide (Martin et al., 1999; Priller et al., 1995). In addition we have investigated: methanandamide; anandamide (18 : 2, n-6) (AEA 18 : 2) (Martin et al., 1999); the anandamide transport inhibitor, AM404; the hybrid vanilloid/cannabinoid activator, ‘arvanil' (Melck et al., 1999) and the irreversible CB1 Receptor antagonist, MAFP (Fernando & Pertwee, 1997). We have also investigated the relative extent to which anandamide interacts with CB1 and vanilloid Receptors in a tissue that appears to express both these Receptor types naturally. This tissue is the mouse vas deferens, a preparation in which anandamide and other CB1 Receptor Agonists serve as potent inhibitors of electrically-evoked contractions (Pertwee, 1997; Rinaldi-Carmona et al., 1994). Results from previous experiments suggest that anandamide can act through pre-junctional CB1 Receptors to produce its inhibitory effects on the mouse vas deferens (Rinaldi-Carmona et al., 1994). In the present investigation we have obtained evidence that this tissue expresses vanilloid Receptors that can mediate inhibition of electrically-evoked contractions and that the inhibitory effect of anandamide on contractions of the mouse vas deferens is mediated by vanilloid Receptors as well as by CB1 Receptors. The extent to which vanilloid Receptors contribute to the inhibitory effects on evoked contractions of the mouse vas deferens of two anandamide analogues, methanandamide and arvanil (Figure 1), and of the non-eicosanoid cannabinoid Receptor agonist, (+)-WIN55212 (Pertwee, 1999), has also been investigated.
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Evidence for the presence of CB1 cannabinoid Receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid Receptors
Life Sciences, 1999Co-Authors: Roger G. PertweeAbstract:The discovery of CB1 and CB2 Receptors and of endogenous Agonists for these Receptors has sparked renewed interest in the therapeutic potential of cannabinoids. This has led to a need for strategies that will provide a better separation of wanted from unwanted effects, particularly for CB1 Receptor Agonists. Possible strategies are to target CB1 Receptors present on neurones outside the central nervous system or novel types or subtypes of neuronal cannabinoid Receptor. This paper reviews evidence for the presence of CB1 Receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid Receptors.
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The bioassay of cannabinoids using the mouse isolated vas deferens.
Marijuana and Cannabinoid Research, 1Co-Authors: Adèle Thomas, Roger G. PertweeAbstract:The mouse isolated vas deferens is a nerve-smooth muscle preparation that serves as a highly sensitive and quantitative functional in vitro bioassay for cannabinoid CB1 Receptor Agonists. Additionally, it is commonly used as a bioassay for competitive surmountable CB1 Receptor antAgonists, and also provides a means for distinguishing neutral CB1 antAgonists from CB1 inverse Agonists. The bioassay of CB1 Receptor Agonists relies on the ability of these ligands to produce concentration-related decreases in the amplitude of electrically evoked contractions of the vas deferens. This they do by acting on naturally expressed prejunctional neuronal CB1 Receptors to inhibit release of the contractile neurotransmitters, noradrenaline and ATP, that is provoked by the electrical stimulation. The bioassay of competitive surmountable CB1 Receptor antAgonists involves determining the ability of these compounds to produce parallel dextral shifts in CB1 Receptor agonist log concentration-response curves in electrically stimulated tissues. The mouse vas deferens has also been used to measure the ability of anandamide to activate vanilloid (TRPV1) Receptors, to monitor modulation by cannabinoids such as 6"-azido-2"-yne-cannabidiol and abnormal cannabidiol of contractions elicited in electrically unstimulated tissues by Agonists for P2X purinoceptors or alpha1-adrenoceptors, and as a bioassay for the nonpsychoactive plant cannabinoid cannabidiol.