The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Feb 2012
The basic property of Lys385 is important for potentiation of the human α1 glycine receptor by ethanol.
Ethanol alters the function of several members of the Cys-loop ligand-gated ion channel superfamily. Recent studies have shown that the sensitivity of the α1 glycine receptor (GlyR) to ethanol can be affected by the state of G protein activation mediated by the interaction of Gβγ with intracellular amino acids in the GlyR. Here, we evaluated the physicochemical property of Lys385 that contributes to ethanol modulation by using mutagenesis, patch-clamp, and biochemical techniques. ⋯ Furthermore, mutations with a hydrophobic leucine (K385L), a hydrogen bond donor glutamine (K385Q), or a neutral residue (K385A) also reduced ethanol modulation. Finally, substitution by a large and hydrophobic residue (K385F) and deletion of 385 (Lys385_) reduced ethanol modulation to 10 ± 4 and 17 ± 0.4%, respectively. Experiments using dynamic cysteine substitution with a methanethiosulfonate reagent and homology modeling indicate that the basic property and the position of Lys385, probably because of its interaction with Gβγ, is critical for ethanol potentiation of the receptor.
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J. Pharmacol. Exp. Ther. · Feb 2012
Comparative StudyChronic methadone treatment shows a better cost/benefit ratio than chronic morphine in mice.
Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. ⋯ Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading μ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.
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J. Pharmacol. Exp. Ther. · Feb 2012
3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism.
The prototypic cannabinoid type 1 (CB₁) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB₁-selective compounds and explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. ⋯ Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ⁹-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB₁⁻/⁻ mice, and they failed to stimulate guanosine-5'-O-(3-[³⁵S]thio)-triphosphate binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB₁-selective cannabinoids that produce agonist-like effects in mice through a non-CB₁, non-CB₂ mechanism.
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J. Pharmacol. Exp. Ther. · Feb 2012
Randomized Controlled TrialEffects of the α₂-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers.
The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α₂-adrenergic receptor agonist clonidine (150 μg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. ⋯ Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α₂-adrenergic receptor agonists in the prevention of psychostimulant dependence.
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J. Pharmacol. Exp. Ther. · Feb 2012
Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure.
Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a "binge" treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. ⋯ It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of binge-induced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers.