Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.

3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity.

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.

Synergistic interactions between the dual serotonergic, noradrenergic reuptake inhibitor duloxetine and the non-steroidal anti-inflammatory drug ibuprofen in inflammatory pain in rodents.

Objectives: The present study was undertaken to characterize whether the pharmacologic interaction between duloxetine, a balanced serotonergic and noradrenergic reuptake inhibitor, and the non-steroidal anti-inflammatory drug ibuprofen was simply additive, less than additive, or greater than additive (i.e., synergistic) in preclinical models of visceral and inflammatory pain, specifically acetic acid-induced writhing in mice and carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats.

Anticonvulsant effects of LY456236, a selective mGlu1 receptor antagonist.

Several lines of evidence suggest that mGlu1 metabotropic glutamate receptors may be involved in seizure disorders such as epilepsy. For example, the mGlu1 agonist DHPG produces limbic seizures and group I antagonists such as 4C3HPG and 4CPG are anticonvulsant when administered intracerebrally. The purpose of the present experiments was to characterize the anticonvulsant effects of the selective mGlu1 receptor antagonist LY456236 in mice and rats.

Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats.

The purpose of the present studies was to compare anticonvulsant drugs with diverse mechanisms of action in a persistent pain model, the formalin test. In addition, the anticonvulsant effects of the compounds were determined in the threshold electroshock tonic seizure test and the 6-Hz limbic seizure test. The effects of the compounds were also determined on locomotor activity.

Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents.

Duloxetine, a selective but balanced serotonergic and noradrenergic reuptake inhibitor, was evaluated in the acute nociceptive pain models of tail flick and hot plate in mice and in the persistent and/or inflammatory pain models of acetic acid-induced writhing in mice, carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats, and capsaicin-induced mechanical allodynia in rats. In acute pain models, duloxetine had no significant effect on response latency in the mouse tail-flick test but produced modest increases in response latencies in the mouse hot plate test. Morphine produced dose-related analgesic effects in both the mouse tail-flick and hot plate tests.

Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models.

Glutamatergic ionotropic and metabotropic receptor modulators have been shown to produce anticonvulsant activity in a number of animal seizure models, e.g. maximal electroshock (MES) and DBA/2 sensory-induced seizures.

Antihyperalgesic effects of the muscarinic receptor ligand vedaclidine in models involving central sensitization in rats.

It is well established that muscarinic cholinergic agonists produce antinociceptive effects in a number of acute pain models. However, relatively little is known about the effects of muscarinic receptor agonists in models which involve central sensitization in pain pathways. The purpose of the present studies was to evaluate the effects of vedaclidine, a muscarinic receptor mixed agonist/antagonist across receptor subtypes, in models involving central sensitization.