The Journal of pharmacology and experimental therapeutics
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To obtain benzomorphans with a longer duration of action that may be potential therapeutics for treating cocaine abuse, 8-carboxamidocyclazocine was synthesized. The pharmacological properties of 8-carboxamidocyclazocine were compared with the parent compound cyclazocine. Changing the 8-hydroxyl group on cyclazocine to an 8-carboxamido group resulted in only a 2-fold decrease in the affinity of the compound for the kappa-receptor, and no change in the affinity for the mu-opioid receptor, with both compounds having K(i) values of less than 1 nM, based on radioligand binding assays. ⋯ Cyclazocine acted as a mu-antagonist in addition to its agonist properties at the mu-receptor, as measured by the inhibition of morphine-induced antinociception. In contrast, 8-carboxamidocyclazocine did not inhibit morphine-induced antinociception, demonstrating that it was not a mu-opioid receptor antagonist in this assay. An i.p. injection of an ED(70) dose of 8-carboxamidocyclazocine produced antinociception that lasted for 15 h in contrast to cyclazocine, which produced antinociception, lasting 2 h. 8-Carboxamidocyclazocine is a novel, long-acting benzomorphan, which possesses pharmacological properties that are distinct from the properties of cyclazocine.
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J. Pharmacol. Exp. Ther. · Jul 2002
Characterization of the diarylether sulfonylester (-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties.
(-)-(R)-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) is a new high-affinity cannabinoid receptor subtype 1 (CB1 receptor) ligand (K(i) = 0.46-1.85 nM; rat brain, human cortex, or recombinant human CB1 receptor), structurally unrelated to any cannabinoid receptor ligand known so far. BAY 38-7271 was characterized as a CB1 receptor agonist in 5-[gamma(35)S]-thiophosphate triethylammonium salt binding assays using rat or human CB1 receptors. In the rat hypothermia assay, BAY 38-7271 induced a dose-dependent reduction in body temperature (minimal effective dose = 6 microg/kg, i.v.); whereas in rats trained to discriminate the CB1/CB2 receptor agonist (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.03 mg/kg, i.p.) from vehicle, BAY 38-7271 induced complete generalization (3 microg/kg, i.v.). ⋯ Even when applied with a 3-h delay, a significant neuroprotective efficacy could be observed (59% infarct volume reduction at 300 ng/kg/h). The neuroprotective potential of BAY 38-7271 was confirmed in a rat model of focal cerebral ischemia induced by permanent occlusion of the middle cerebral artery. It is concluded that the CB1/CB2 receptor agonist BAY 38-7271 shows pronounced neuroprotective properties that do not result from drug-induced hypothermia and that occur in a dose range devoid of typical cannabinoid-like side effects.
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J. Pharmacol. Exp. Ther. · Jul 2002
Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo.
Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance oleamide. Both anandamide and oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro. Accordingly, oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and inhibiting the degradation of endogenous anandamide. ⋯ Contrary to both oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(+/+) and (-/-) mice. Collectively, these results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo. More generally, these findings suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo.
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J. Pharmacol. Exp. Ther. · Jul 2002
Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages.
Silymarin, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects. In the present study, we report the inhibitory effect of silymarin on nitric oxide production and inducible nitric-oxide synthase (iNOS) gene expression in macrophages. In vivo administration of silymarin attenuated nitric oxide production by peritoneal macrophages in lipopolysaccharide (LPS)-treated mice. ⋯ Further study showed that silymarin suppressed the production of reactive oxygen species generated by H(2)O(2) in RAW 264.7 cells. Collectively, these results suggest that silymarin inhibits nitric oxide production and iNOS gene expression by inhibiting NF-kappaB/Rel activation. Furthermore, the radical-scavenging activity of silymarin may explain its inhibitory effect on NF-kappaB/Rel activation.
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J. Pharmacol. Exp. Ther. · Jun 2002
Comparative StudyZidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey.
We measured zidovudine concentrations in blood, muscle, and brain extracellular fluid (ECF) by microdialysis and in serum ultrafiltrate and cerebrospinal fluid (CSF) samples during a continuous intravenous infusion (15 mg/kg/h) and after bolus dosing (50-80 mg/kg over 15 min) in nonhuman primates to determine whether CSF drug penetration is a valid surrogate for blood-brain barrier penetration. Recovery was estimated in vivo by zero net flux for the continuous infusion and retrodialysis for the bolus dosing. In vivo recovery was tissue-dependent and was lower in brain than in blood or muscle. ⋯ In conclusion, recovery was tissue-dependent. CSF and brain ECF zidovudine concentrations were comparable at steady state, and the corresponding AUCs were comparable after bolus injection. Thus, zidovudine penetration in brain ECF and CSF in nonhuman primates is limited to a similar extent, presumably by active transport, as in other species.