The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Feb 2001
In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor.
JTE-907 [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] was evaluated in vitro and in vivo as a novel selective ligand for cannabinoid receptor of peripheral type (CB2). The compound binds with high affinity to human CB2 or mouse CB2 expressed on CHO cell membrane and to rat CB2 on splenocytes. The K(i) affinities for human, mouse, and rat CB2 were 35.9, 1.55, and 0.38 nM, respectively. ⋯ JTE-907 dosed orally inhibited carrageenin-induced mouse paw edema dose dependently. The same in vivo effect was observed with other cannabinoid receptor ligands such as SR144528, Delta(9)-tetrahydrocannabinol (THC), and Win55212-2. This is the first report that a CB2-selective inverse agonist, JTE-907, has an anti-inflammatory effect in vivo, and how the inverse agonist showed the same effect as Win55212-2 and Delta(9)-THC is discussed.
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J. Pharmacol. Exp. Ther. · Jan 2001
mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors.
The effect of selective group I metabotropic glutamate receptor subtype 5 (mGluR5) antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB-1893) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. Treatment with MPEP and SIB-1893 showed significant neuroprotective effects in rat cortical neuronal cultures subjected to mechanical injury. Application of the antagonists also attenuated glutamate- and N-methyl-D-aspartate (NMDA)-induced neuronal cell death in vitro. ⋯ Lesion volumes as assessed by magnetic resonance imaging were also substantially reduced by MPEP treatment. Although we show that MPEP acts as a potent mGluR5 antagonist in our culture system, where it completely blocks agonist-induced phosphoinositide hydrolysis, electrophysiological and pharmacological studies indicate that MPEP and SIB-1893 also inhibit NMDA receptor activity at higher concentrations that are neuroprotective. Taken together, these data suggest that MPEP and SIB-1893 may have therapeutic potential in brain injury, although the mechanisms of neuroprotective action for these drugs may reflect their ability to modulate NMDA receptor activity.
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J. Pharmacol. Exp. Ther. · Jan 2001
A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice.
Brain injury induces disruption of the blood-brain barrier, edema, and release of autodestructive factors that produce delayed neuronal damage. NAPSVIPQ (NAP), a femtomolar-acting peptide, is shown to be neuroprotective in a mouse model of closed head injury. NAP injection after injury reduced mortality and facilitated neurobehavioral recovery (P < 0.005). ⋯ Furthermore, in vivo magnetic resonance imaging demonstrated significant brain-tissue recovery in the NAP-treated animals. NAP treatment decreased tumor necrosis factor-alpha levels in the injured brain and was shown to protect pheochromocytoma (PC12 cells) against tumor necrosis factor-alpha-induced toxicity. Thus, NAP provides significant amelioration from the complex array of injuries elicited by head trauma.
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J. Pharmacol. Exp. Ther. · Dec 2000
Supraspinal antinociceptive response to [D-Pen(2,5)]-enkephalin (DPDPE) is pharmacologically distinct from that to other delta-agonists in the rat.
The cloned delta-opioid receptor (DOR) is being investigated as a potential target for novel analgesics with an improved safety profile over mu-opioid receptor agonists such as morphine. The current study used antisense techniques to evaluate the role of DOR in mediating supraspinal antinociception in rats. All of the opioid agonists tested (delta-selective: deltorphin II, DPDPE, pCl-DPDPE, SNC80; mu-selective: DAMGO; i.c.v.) provided significant, dose-dependent antinociception in the paw pressure assay. ⋯ In total, these data suggest that DOR mediates the antinociceptive response to deltorphin II, SNC80, and pCl-DPDPE at supraspinal sites and further demonstrates that the DOR-mediated response to deltorphin II and SNC80 is independent of mu-receptor activation. Conversely, supraspinal antinociception in response to DPDPE is mediated by a receptor distinct from DOR; this response is directly or indirectly sensitive to mu-receptor blockade. The distinct pharmacological profile of DPDPE suggests that either this prototypical delta-agonist mediates antinociception by a direct, nonselective interaction at mu-receptors or DPDPE interacts with a novel delta-subtype that, in turn, indirectly activates mu-receptors in the brain.
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J. Pharmacol. Exp. Ther. · Dec 2000
ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat.
Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC(50) = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ⋯ In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30-300 micromol/kg p.o.), mean arterial pressure (at 30-100 micromol/kg p.o.), or exploratory locomotor activity (at