R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (mark... more R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (marketed as Spravato for depression). Recent data have suggested (R)-ketamine could have value in the treatment of substance use disorder. The present set of experiments was undertaken to examine whether (R)-ketamine might prevent tolerance development. Rapid ethanol (ETOH) tolerance was studied since racemic ketamine had previously been shown to block this tolerance development in rats. In the present study, male Sprague-Dawley rats were given two large doses of ETOH on Day 1 (2.3 + 1.7 g/kg) and 2.3 g/kg ETOH on Day 2. Animals were tested for effects of 2.3 g/kg ETOH on grip strength, inclined screen performance and rotarod performance on Day 1 with or without (R)-ketamine as a pretreatment. (R)-ketamine alone was tested at the highest dose studied (10 mg/kg) and did not significantly influence any dependent measure. (R)-ketamine (1-10 mg/kg) did not alter the acute effects of ETOH except for enhancing the effects of ETOH on the inclined screen test at 3 mg/kg. Between-subjects analysis documented that tolerance developed to the effects of ETOH only on the measure of grip strength. (R)-ketamine (3 mg/kg) given prior to ETOH on Day 1 exhibited a strong trend toward preventing tolerance development (p=0.062). The present results extend prior findings on the potential value of (R)-ketamine in substance abuse disorder and add to the literature on NMDA receptor blockade as a tolerance-regulating mechanism.
HZ-166 has previously been characterized as an α2,3-selective GABA receptor modulator with antico... more HZ-166 has previously been characterized as an α2,3-selective GABA receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity. KRM-II-81 was active against electroshock-induced convulsions in mice, pentylenetetrazole (PTZ)-induced convulsions in rats, elevations in PTZ-seizure thresholds, and amygdala-kindled seizures in rats with efficacies greater than that of diazepam. KRM-II-81 was also active in the 6 Hz seizure model in mice. Structural analogs of KRM-II-81 but not the ester, HZ-166, were active in al...
Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of... more Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAreceptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments. We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis. In the forced-swim assay in mice that detects antidepressant drugs, the α5β3γ2 GABAreceptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5β3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5β3γ2 receptor antagonist, Xli-093...
Pharmacology, biochemistry, and behavior, Jun 22, 2017
Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects includin... more Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5-a][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of the three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam. Compounds 7 and 8, ester bioisosters, were selective for alpha 2 and 3 over alpha 1-containing GABAA receptors but also had modest efficacy at GABAA alpha 5-containing receptors. Compound 7 was efficacious and potent in this anxiolytic-detecting assay without affecting non-punished responding. The efficacies of the esters and of compound 7 were predicted from their efficacies as anticonvulsants against the GABAA antagonist pentylenetetrazole (PTZ). In...
The Journal of pharmacology and experimental therapeutics, 1987
The ability of various treatments to prevent peripheral parasympathetic actions, central effects ... more The ability of various treatments to prevent peripheral parasympathetic actions, central effects and lethality of the muscarinic agonist oxotremorine was studied in rats. The percentage of animals exhibiting effects of oxotremorine was dose and time dependent. The ED50 for producing lacrimation, salivation, tremor, convulsions and death was 2.5, 1.3, 1.6, 3.2 and 8.3 mg/kg i.p., respectively. Pretreatment with 5 mg/kg of atropine completely prevented all observable effects of oxotremorine at doses of 5 mg/kg and below. Doses of oxotremorine in excess of 5 mg/kg produced tremor, generalized clonic convulsions and death that could not be prevented by atropine when given at up to 160 mg/kg; lacrimation and salivation were not present in atropine-treated rats. In the presence of 40 mg/kg of atropine, ED50 values for oxotremorine were shifted more than 12-fold for lacrimation, salivation and tremor, whereas convulsions and death were maximally altered by a factor of 2. Scopolamine, benac...
The Journal of pharmacology and experimental therapeutics, 1987
In vitro potencies of a series of muscarinic antagonists were compared with their effects on oper... more In vitro potencies of a series of muscarinic antagonists were compared with their effects on operant behavior. Ki values for inhibition of [3H]N-methylscopolamine binding in N4TG1 neuroblastoma cells correlated positively with ED50 values for the inhibition of carbachol-induced alpha-amylase release from pancreatic acini cells and with KB values for inhibition of acetylcholine-induced contractions of guinea pig ileum. The rank order of potency for inhibition of [3H]N-methylscopolamine binding was quinuclidinyl benzilate = quinuclidinyl xanthene-9-carboxylate greater than (methyl atropine = atropine) greater than benactyzine greater than azaprophen greater than (adiphenine = aprophen) greater than pirenzepine greater than ethyl aprophen. The M1 antagonist, pirenzepine, was a weak inhibitor in the guinea pig ileum and alpha-amylase assays relative to its ability to inhibit [3H]N-methylscopolamine binding; azaprophen exhibited the opposite relationship. Lever-press responses of rats we...
R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (mark... more R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (marketed as Spravato for depression). Recent data have suggested (R)-ketamine could have value in the treatment of substance use disorder. The present set of experiments was undertaken to examine whether (R)-ketamine might prevent tolerance development. Rapid ethanol (ETOH) tolerance was studied since racemic ketamine had previously been shown to block this tolerance development in rats. In the present study, male Sprague-Dawley rats were given two large doses of ETOH on Day 1 (2.3 + 1.7 g/kg) and 2.3 g/kg ETOH on Day 2. Animals were tested for effects of 2.3 g/kg ETOH on grip strength, inclined screen performance and rotarod performance on Day 1 with or without (R)-ketamine as a pretreatment. (R)-ketamine alone was tested at the highest dose studied (10 mg/kg) and did not significantly influence any dependent measure. (R)-ketamine (1-10 mg/kg) did not alter the acute effects of ETOH except for enhancing the effects of ETOH on the inclined screen test at 3 mg/kg. Between-subjects analysis documented that tolerance developed to the effects of ETOH only on the measure of grip strength. (R)-ketamine (3 mg/kg) given prior to ETOH on Day 1 exhibited a strong trend toward preventing tolerance development (p=0.062). The present results extend prior findings on the potential value of (R)-ketamine in substance abuse disorder and add to the literature on NMDA receptor blockade as a tolerance-regulating mechanism.
HZ-166 has previously been characterized as an α2,3-selective GABA receptor modulator with antico... more HZ-166 has previously been characterized as an α2,3-selective GABA receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity. KRM-II-81 was active against electroshock-induced convulsions in mice, pentylenetetrazole (PTZ)-induced convulsions in rats, elevations in PTZ-seizure thresholds, and amygdala-kindled seizures in rats with efficacies greater than that of diazepam. KRM-II-81 was also active in the 6 Hz seizure model in mice. Structural analogs of KRM-II-81 but not the ester, HZ-166, were active in al...
Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of... more Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAreceptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments. We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis. In the forced-swim assay in mice that detects antidepressant drugs, the α5β3γ2 GABAreceptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5β3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5β3γ2 receptor antagonist, Xli-093...
Pharmacology, biochemistry, and behavior, Jun 22, 2017
Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects includin... more Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5-a][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of the three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam. Compounds 7 and 8, ester bioisosters, were selective for alpha 2 and 3 over alpha 1-containing GABAA receptors but also had modest efficacy at GABAA alpha 5-containing receptors. Compound 7 was efficacious and potent in this anxiolytic-detecting assay without affecting non-punished responding. The efficacies of the esters and of compound 7 were predicted from their efficacies as anticonvulsants against the GABAA antagonist pentylenetetrazole (PTZ). In...
The Journal of pharmacology and experimental therapeutics, 1987
The ability of various treatments to prevent peripheral parasympathetic actions, central effects ... more The ability of various treatments to prevent peripheral parasympathetic actions, central effects and lethality of the muscarinic agonist oxotremorine was studied in rats. The percentage of animals exhibiting effects of oxotremorine was dose and time dependent. The ED50 for producing lacrimation, salivation, tremor, convulsions and death was 2.5, 1.3, 1.6, 3.2 and 8.3 mg/kg i.p., respectively. Pretreatment with 5 mg/kg of atropine completely prevented all observable effects of oxotremorine at doses of 5 mg/kg and below. Doses of oxotremorine in excess of 5 mg/kg produced tremor, generalized clonic convulsions and death that could not be prevented by atropine when given at up to 160 mg/kg; lacrimation and salivation were not present in atropine-treated rats. In the presence of 40 mg/kg of atropine, ED50 values for oxotremorine were shifted more than 12-fold for lacrimation, salivation and tremor, whereas convulsions and death were maximally altered by a factor of 2. Scopolamine, benac...
The Journal of pharmacology and experimental therapeutics, 1987
In vitro potencies of a series of muscarinic antagonists were compared with their effects on oper... more In vitro potencies of a series of muscarinic antagonists were compared with their effects on operant behavior. Ki values for inhibition of [3H]N-methylscopolamine binding in N4TG1 neuroblastoma cells correlated positively with ED50 values for the inhibition of carbachol-induced alpha-amylase release from pancreatic acini cells and with KB values for inhibition of acetylcholine-induced contractions of guinea pig ileum. The rank order of potency for inhibition of [3H]N-methylscopolamine binding was quinuclidinyl benzilate = quinuclidinyl xanthene-9-carboxylate greater than (methyl atropine = atropine) greater than benactyzine greater than azaprophen greater than (adiphenine = aprophen) greater than pirenzepine greater than ethyl aprophen. The M1 antagonist, pirenzepine, was a weak inhibitor in the guinea pig ileum and alpha-amylase assays relative to its ability to inhibit [3H]N-methylscopolamine binding; azaprophen exhibited the opposite relationship. Lever-press responses of rats we...
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Papers by Jeffrey Witkin