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Samuel D Banister - One of the best experts on this subject based on the ideXlab platform.
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the chemistry and pharmacology of putative synthetic Cannabinoid Receptor Agonist scra new psychoactive substances nps 5f py pica 5f py pinaca and their analogs
Drug Testing and Analysis, 2019Co-Authors: Samuel D Banister, Richard C Kevin, Lewis J Martin, Axel Adams, Christa Macdonald, Jamie J Manning, Rochelle Boyd, Michael J Cunningham, Marc Y StevensAbstract:5F-PY-PICA and 5F-PY-PINACA are pyrrolidinyl 1-(5-fluoropentyl)ind (az)ole-3-carboxamides identified in 2015 as putative synthetic Cannabinoid Receptor Agonist (SCRA) new psychoactive substances (NPS). 5F-PY-PICA, 5F-PY-PINACA, and analogs featuring variation of the 1-alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS). In competitive binding experiments against HEK293 cells expressing human Cannabinoid Receptor type 1 (hCB1 ) or type 2 (hCB2 ), all analogs showed minimal affinity for CB1 (pKi 50% of the classical Cannabinoid Agonist CP55,940 (at 1 μM) at hCB1 , although several showed slightly higher relative efficacy at hCB2 . Expansion of the pyrrolidine ring of 5F-PY-PICA to an azepane (8) conferred the greatest hCB2 affinity (pKi 6.99) and activity (pEC50 7.54, Emax 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F-PY-PICA and 5F-PY-PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.
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the chemistry and pharmacology of putative synthetic Cannabinoid Receptor Agonist scra new psychoactive substances nps 5f py pica 5f py pinaca and their analogues
bioRxiv, 2018Co-Authors: Samuel D Banister, Richard C Kevin, Lewis J Martin, Axel Adams, Christa Macdonald, Jamie J Manning, Rochelle Boyd, Michael J Cunningham, Marc Y Stevens, Iain S McgregorAbstract:The structural diversity of synthetic Cannabinoid Receptor Agonist (SCRA) new psychoactive substances (NPS) has increased since the first examples were reported a decade ago. 5F-PY-PICA and 5F-PY-PINACA were identified in 2015 as putative SCRA NPS, although nothing is known of their pharmacology. 5F-PY-PICA, 5F-PY-PINACA, and analogues intended to explore structure-activity relationships within this class of SCRAs were synthesized and characterized by nuclear magnetic resonance spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry. Using competitive binding experiments and fluorescence-based plate reader membrane potential assays, the affinities and activities of all analogues at Cannabinoid type 1 and type 2 Receptors (CB 1 and CB 2 ) were evaluated. All ligands showed minimal affinity for CB 12 (p K i 2 binding (p K i = 5.45-6.99). At 10 μM none of the compounds produced an effect >50% of CP55,950 at CB 1 , while several compounds showed a slightly higher relative efficacy at CB 2 . Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.
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the chemistry and pharmacology of synthetic Cannabinoid Receptor Agonist new psychoactive substances evolution
Handbook of experimental pharmacology, 2018Co-Authors: Samuel D Banister, Mark ConnorAbstract:Synthetic Cannabinoid Receptor Agonists (SCRAs) are the largest and most structurally diverse class of new psychoactive substances (NPS). Although the earliest SCRA NPS were simply repurposed from historical academic manuscripts or pharmaceutical patents describing Cannabinoid ligands, recent examples bear hallmarks of rational design. SCRA NPS manufacturers have applied traditional medicinal chemistry strategies (such as molecular hybridization, bioisosteric replacement, and scaffold hopping) to existing Cannabinoid templates in order to generate new molecules that circumvent structure-based legislation. Most SCRAs potently activate Cannabinoid type 1 and type 2 Receptors (CB1 and CB2, respectively), with the former contributing to the psychoactivity of these substances. SCRAs are generally more toxic than the Δ9-tetrahydrocannabinol (Δ9-THC) found in cannabis, and this may be due to ligand bias, metabolism, or off-target activity. This chapter will chart the evolution of recently identified SCRA NPS chemotypes, as well as their putative manufacturing by-products and thermolytic degradants, and describe structure-activity relationships within each class.
Iain S Mcgregor - One of the best experts on this subject based on the ideXlab platform.
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the chemistry and pharmacology of putative synthetic Cannabinoid Receptor Agonist scra new psychoactive substances nps 5f py pica 5f py pinaca and their analogues
bioRxiv, 2018Co-Authors: Samuel D Banister, Richard C Kevin, Lewis J Martin, Axel Adams, Christa Macdonald, Jamie J Manning, Rochelle Boyd, Michael J Cunningham, Marc Y Stevens, Iain S McgregorAbstract:The structural diversity of synthetic Cannabinoid Receptor Agonist (SCRA) new psychoactive substances (NPS) has increased since the first examples were reported a decade ago. 5F-PY-PICA and 5F-PY-PINACA were identified in 2015 as putative SCRA NPS, although nothing is known of their pharmacology. 5F-PY-PICA, 5F-PY-PINACA, and analogues intended to explore structure-activity relationships within this class of SCRAs were synthesized and characterized by nuclear magnetic resonance spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry. Using competitive binding experiments and fluorescence-based plate reader membrane potential assays, the affinities and activities of all analogues at Cannabinoid type 1 and type 2 Receptors (CB 1 and CB 2 ) were evaluated. All ligands showed minimal affinity for CB 12 (p K i 2 binding (p K i = 5.45-6.99). At 10 μM none of the compounds produced an effect >50% of CP55,950 at CB 1 , while several compounds showed a slightly higher relative efficacy at CB 2 . Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.
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pre exposure to the Cannabinoid Receptor Agonist cp 55 940 enhances morphine behavioral sensitization and alters morphine self administration in lewis rats
European Journal of Pharmacology, 2003Co-Authors: Christy S Norwood, Jennifer L Cornish, Paul E Mallet, Iain S McgregorAbstract:Three experiments examined the influence of pre-exposure to the Cannabinoid Receptor Agonist CP 55,940 ((−)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol) on the sensitization of morphine-induced locomotor hyperactivity and self-administration in Lewis rats. In Experiment 1, rats received daily injections of vehicle or CP 55,940 (0.1 mg/kg for 7 days then 0.2 mg/kg for a further 7 days). Four weeks later, the locomotor response to morphine (10 mg/kg s.c.) was tested once per day over a 3-h period for 14 consecutive days. Rats given morphine showed hypoactivity during the first hour following morphine but hyperactivity during the second and third hours. A progressive increase in hyperactivity to morphine was seen over the 14 days of administration, which was significantly greater in rats pre-treated with CP 55,940. In Experiment 2, rats were given morphine (10 mg/kg) once a day for 14 days in combination with either vehicle, CP 55,940 (0.1 mg/kg) or the Cannabinoid CB1 Receptor antAgonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (3 mg/kg). Both CP 55,940 and SR 141716 initially inhibited the hyperactive response to morphine, but these effects gradually wore off and by the end of 14 days, hyperactivity was similar in all morphine-treated groups. When tested 3 weeks later for their response to morphine (10 mg/kg) given alone, rats previously given the morphine/CP 55,940 combination, but not the SR 141716/morphine combination, showed a greater locomotor stimulation than those previously exposed to morphine only. In Experiment 3, rats were pre-exposed to CP 55,940 or vehicle for 14 days and were subsequently trained to self-administer morphine intravenously (1 mg/kg per lever press) for 14 days. Rats pre-exposed to CP 55,940 self-administered a significantly greater number of morphine infusions than vehicle pre-exposed rats. However, both active and inactive (‘dummy’) lever presses were increased by Cannabinoid pre-treatment. Overall, these results suggest that Cannabinoid pre-exposure can lead to an exaggeration of morphine-induced hyperactivity and may alter the reinforcing effects of morphine in Lewis rats. The implications for ‘gateway’ theories of Cannabinoid effects in humans are discussed.
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effects of the Cannabinoid Receptor Agonist cp 55 940 and the Cannabinoid Receptor antAgonist sr 141716 on intracranial self stimulation in lewis rats
Life Sciences, 2001Co-Authors: Jonathon C Arnold, Glenn E Hunt, Iain S McgregorAbstract:Abstract Lewis rats were trained to self-stimulate the medial forebrain bundle (MFB) using a rate-frequency paradigm. They were then tested for the effects of the Cannabinoid Receptor Agonist CP 55,940, the selective Cannabinoid Receptor antAgonist SR 141716 and the dopamine D 1 Receptor antAgonist SCH 23390. CP 55,940 (0, 10, 25 and 50 μg/kg i.p.) had no effect on MFB self-stimulation behaviour as assessed by the M 50 , the stimulation frequency at which half-maximal response rates were obtained. With SR 141716, only a very high dose (20 mg/kg i.p.) caused a significant inhibition of the rewarding efficacy of the stimulation. This was seen as an increase in the M 50 . All other doses of SR 141716 (0, 1, 3, 10 mg/kg i.p.) were ineffective in modulating the M 50 . By comparison, a relatively low dose (0.06 mg/kg i.p.) of SCH 23390 caused a large increase in M 50 . These results indicate a relatively modest influence, if any at all, of exogenous or endogenous Cannabinoids on reward-relevant neurotransmission.
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effects of pre exposure and co administration of the Cannabinoid Receptor Agonist cp 55 940 on behavioral sensitization to cocaine
European Journal of Pharmacology, 1998Co-Authors: Jonathon C Arnold, Ann N Topple, Glenn E Hunt, Iain S McgregorAbstract:Rats given cocaine (15 mg/kg, i.p.) every second day over a 2-week period displayed a progressively greater locomotor response to the drug over days indicating behavioral sensitization. When the Cannabinoid Receptor Agonist CP 55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl)cyclohexanol) (10, 25 or 50 microg/kg) was administered under a similar regime, no such sensitization was observed. Rather, the two highest doses of CP 55,940 (25 and 50 microg/kg) caused locomotor suppression that lasted throughout administration. When rats pre-exposed 10 times to CP 55,940 were challenged with cocaine (15 mg/kg), no exaggerated locomotor response to cocaine was evident relative to non pre-exposed rats. When these rats were subsequently re-tested with CP 55,940, the Cannabinoid continued to produce a dose-dependent suppression of locomotor activity. Finally, when CP 55,940 (50 microg/kg) was co-administered with cocaine, it significantly reduced the locomotor hyperactivity produced by the drug but did not block the development of behavioral sensitization. These results show that CP 55,940 does not sensitize locomotor activity with repeated administration in the same way as cocaine, and that pre-exposure or concurrent exposure to CP 55,940 does not enhance sensitivity to the subsequent behavioral effects of cocaine.
Junzo Kamei - One of the best experts on this subject based on the ideXlab platform.
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Antitussive effect of WIN 55212-2, a Cannabinoid Receptor Agonist.
European journal of pharmacology, 2003Co-Authors: Kayo Morita, Junzo KameiAbstract:Several lines of evidence indicate that the opioid and Cannabinoid systems produce synergistic interactions. The present study examined the opioid Receptors involved in the antitussive effect of WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate), a high-affinity Cannabinoid Receptor Agonist, in mice. WIN 55212-2, at doses of 0.3-3 mg/kg ip, produced a dose-dependent antitussive effect. This antitussive effect of WIN 55212-2 was antagonized by pretreatment with either methysergide (3 mg/kg ip), a 5-HT Receptor antAgonist, or naloxone (1 mg/kg ip), an opioid Receptor antAgonist. Furthermore, pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 3 mg/kg ip), a Cannabinoid CB(1) Receptor antAgonist, also significantly reduced the antitussive effect of WIN 55212-2. Blockade of mu-opioid Receptors by pretreatment with beta-funaltrexamine (40 mg/kg sc) significantly reduced the antitussive effect of WIN 55212-2. However, pretreatment with nor-binaltorphimine (20 mg/kg sc), a kappa-opioid Receptor antAgonist, did not affect the antitussive effect of WIN 55212-2. Pretreatment with naloxonazine (35 mg/kg sc), a mu(1)-opioid Receptor antAgonist, also did not affect the antitussive effect of WIN 55212-2. These results indicate that the antitussive effect of WIN 55212-2 is mediated by the activation of Cannabinoid CB(1) Receptors and mu(2) (naloxonazine-insensitive)-opioid Receptors, but not mu(1) (naloxonazine-sensitive)- or kappa-opioid Receptors.
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Antitussive effect of WIN 55212-2, a Cannabinoid Receptor Agonist.
European Journal of Pharmacology, 2003Co-Authors: Kayo Morita, Junzo KameiAbstract:Abstract Several lines of evidence indicate that the opioid and Cannabinoid systems produce synergistic interactions. The present study examined the opioid Receptors involved in the antitussive effect of WIN 55212-2 (( R )-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate), a high-affinity Cannabinoid Receptor Agonist, in mice. WIN 55212-2, at doses of 0.3–3 mg/kg ip, produced a dose-dependent antitussive effect. This antitussive effect of WIN 55212-2 was antagonized by pretreatment with either methysergide (3 mg/kg ip), a 5-HT Receptor antAgonist, or naloxone (1 mg/kg ip), an opioid Receptor antAgonist. Furthermore, pretreatment with N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide hydrochloride (SR141716A, 3 mg/kg ip), a Cannabinoid CB 1 Receptor antAgonist, also significantly reduced the antitussive effect of WIN 55212-2. Blockade of μ-opioid Receptors by pretreatment with β-funaltrexamine (40 mg/kg sc) significantly reduced the antitussive effect of WIN 55212-2. However, pretreatment with nor-binaltorphimine (20 mg/kg sc), a κ-opioid Receptor antAgonist, did not affect the antitussive effect of WIN 55212-2. Pretreatment with naloxonazine (35 mg/kg sc), a μ 1 -opioid Receptor antAgonist, also did not affect the antitussive effect of WIN 55212-2. These results indicate that the antitussive effect of WIN 55212-2 is mediated by the activation of Cannabinoid CB 1 Receptors and μ 2 (naloxonazine-insensitive)-opioid Receptors, but not μ 1 (naloxonazine-sensitive)- or κ-opioid Receptors.
Tiziana Antonelli - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid Receptor Agonist win 55 212 2 inhibits rat cortical dialysate gamma aminobutyric acid levels
Journal of Neuroscience Research, 2001Co-Authors: Luca Ferraro, Maria Cristina Tomasini, Tommaso Cassano, Berta Wonjie Bebe, Anna Siniscalchi, William T Oconnor, Pamela J Magee, Sergio Tanganelli, Vincenzo Cuomo, Tiziana AntonelliAbstract:The effects of the Cannabinoid Receptor Agonist WIN 55,212-2 (0.1-5 mg/kg i.p.) on endogenous extracellular gamma-aminobutyric acid (GABA) levels in the cerebral cortex of the awake rat was investigated by using microdialysis. WIN 55,212-2 (1 and 5 mg/kg i.p.) was associated with a concentration-dependent decrease in dialysate GABA levels (-16% +/- 4% and -26% +/- 4% of basal values, respectively). The WIN 55,212-2 (5 mg/kg i.p.) induced-inhibition was counteracted by a dose (0.1 mg/kg i.p.) of the CB(1) Receptor antAgonist SR141716A, which by itself was without effect on cortical GABA levels. These findings suggest that Cannabinoids decrease cortical GABA levels in vivo, an action that might underlie some of the cognitive and behavioral effects of acute exposure to marijuana.
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the Cannabinoid Receptor Agonist win 55 212 2 regulates glutamate transmission in rat cerebral cortex an in vivo and in vitro study
Cerebral Cortex, 2001Co-Authors: Luca Ferraro, Gian Luigi Gessa, Maria Cristina Tomasini, Berta Wonjie Bebe, Sergio Tanganelli, Tiziana AntonelliAbstract:The effects of the Cannabinoid Receptor Agonist WIN 55,212-2 on endogenous extracellular glutamate levels in the prefrontal cortex of the awake rat and in primary cultures of rat cerebral cortex neurons were investigated. In the prefrontal cortex WIN 55,212-2 (0.1 and 1 mg/kg i.p.) increased dialysate glutamate levels from of the awake rat, while the lower (0.01 mg/kg) and the higher (2 mg/kg) doses were ineffective. Furthermore, the WIN 55,212-2 (0.1 mg/kg)- induced increase of dialysate glutamate levels was counteracted by pretreatment with the selective CB(1) Receptor antAgonist SR141716A (0.1 mg/kg i.p.) and by the local perfusion with a low-calcium Ringer solution (Ca(2+) 0.2 mM). In primary cultures of rat cerebral cortex neurons, WIN 55,212-2 (0.01--100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration-response curve. The facilitatory effect of WIN 55,212-2 (1 nM) was fully counteracted by SR141716A (10 nM), by the replacement of the normal Krebs Ringer-bicarbonate buffer with a low Ca(2+) medium (0.2 mM) and by the IP(3) Receptor antAgonist xestospongin C (1 microM). These in vivo and in vitro findings suggest an increase in cortical glutamatergic transmission by CB(1) Receptors, an effect that may underlie some of the psychoactive and behavioural actions of acute exposure to marijuana.
Marc Y Stevens - One of the best experts on this subject based on the ideXlab platform.
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the chemistry and pharmacology of putative synthetic Cannabinoid Receptor Agonist scra new psychoactive substances nps 5f py pica 5f py pinaca and their analogs
Drug Testing and Analysis, 2019Co-Authors: Samuel D Banister, Richard C Kevin, Lewis J Martin, Axel Adams, Christa Macdonald, Jamie J Manning, Rochelle Boyd, Michael J Cunningham, Marc Y StevensAbstract:5F-PY-PICA and 5F-PY-PINACA are pyrrolidinyl 1-(5-fluoropentyl)ind (az)ole-3-carboxamides identified in 2015 as putative synthetic Cannabinoid Receptor Agonist (SCRA) new psychoactive substances (NPS). 5F-PY-PICA, 5F-PY-PINACA, and analogs featuring variation of the 1-alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS). In competitive binding experiments against HEK293 cells expressing human Cannabinoid Receptor type 1 (hCB1 ) or type 2 (hCB2 ), all analogs showed minimal affinity for CB1 (pKi 50% of the classical Cannabinoid Agonist CP55,940 (at 1 μM) at hCB1 , although several showed slightly higher relative efficacy at hCB2 . Expansion of the pyrrolidine ring of 5F-PY-PICA to an azepane (8) conferred the greatest hCB2 affinity (pKi 6.99) and activity (pEC50 7.54, Emax 72%) within the series. Unlike other SCRA NPS evaluated in vivo using radio biotelemetry, 5F-PY-PICA and 5F-PY-PINACA did not produce cannabimimetic effects (hypothermia, bradycardia) in mice at doses up to 10 mg/kg.
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the chemistry and pharmacology of putative synthetic Cannabinoid Receptor Agonist scra new psychoactive substances nps 5f py pica 5f py pinaca and their analogues
bioRxiv, 2018Co-Authors: Samuel D Banister, Richard C Kevin, Lewis J Martin, Axel Adams, Christa Macdonald, Jamie J Manning, Rochelle Boyd, Michael J Cunningham, Marc Y Stevens, Iain S McgregorAbstract:The structural diversity of synthetic Cannabinoid Receptor Agonist (SCRA) new psychoactive substances (NPS) has increased since the first examples were reported a decade ago. 5F-PY-PICA and 5F-PY-PINACA were identified in 2015 as putative SCRA NPS, although nothing is known of their pharmacology. 5F-PY-PICA, 5F-PY-PINACA, and analogues intended to explore structure-activity relationships within this class of SCRAs were synthesized and characterized by nuclear magnetic resonance spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry. Using competitive binding experiments and fluorescence-based plate reader membrane potential assays, the affinities and activities of all analogues at Cannabinoid type 1 and type 2 Receptors (CB 1 and CB 2 ) were evaluated. All ligands showed minimal affinity for CB 12 (p K i 2 binding (p K i = 5.45-6.99). At 10 μM none of the compounds produced an effect >50% of CP55,950 at CB 1 , while several compounds showed a slightly higher relative efficacy at CB 2 . Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.
