Novel sulfamoyl benzamides as selective CB(2) agonists with improved in vitro metabolic stability.

A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.

Novel pyridine derivatives as potent and selective CB2 cannabinoid receptor agonists.

Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.

Discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB2 agonists.

Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.

CB2 selective sulfamoyl benzamides: optimization of the amide functionality.

Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally.

Sulfamoyl benzamides as novel CB2 cannabinoid receptor ligands.

Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.

Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain.

The identification of peripherally expressed CB2 receptors and reports that the selective activation of cannabinoid CB2 receptors produces antinociception without traditional cannabinergic side effects suggests that selective cannabinoid CB2 receptor agonists might be useful in the management of pain. In a rat hindpaw incision model, we examined the antiallodynic activity of the selective cannabinoid CB2 receptor agonists AM1241 (3-30 mg/kg i.p.

Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain.

Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform-selective inhibitors of NOS have been developed.

Pharmacological evaluation of the selective spinal nerve ligation model of neuropathic pain in the rat.

Rodent models of neuropathic pain are used to investigate the underlying mechanisms of pain associated with damage to peripheral nerves and to evaluate the efficacy of novel compounds. However, few models have been adequately characterized and the validity of many models remains unclear. The present experiment examined the activity of known anti-allodynic compounds in the L5 spinal nerve ligation (SNL) model of peripheral mononeuropathy in the rat, a modified version of the L5/L6 SNL model [S.

Tuberoinfundibular peptide of 39 residues decreases pain-related affective behavior.

Tuberoinfundibular peptide of 39 residues (TIP39) is a recently identified parathyroid hormone 2 receptor ligand. Their CNS distributions suggest potential involvement in neuroendocrine, limbic and sensory processing functions. Herein we investigate the analgesic and antinociceptive actions of brain delivery of TIP39 in adult male rats.

Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain.

Various limbic system structures have been implicated in processing noxious information. One such structure is the anterior cingulate cortex (ACC), a region that is thought to modulate higher order processing of noxious input related to the affective/motivational component of pain. The present experiment examined the involvement of the ACC in higher order pain processing by measuring paw withdrawal threshold and escape/avoidance responses in the L5 spinal nerve ligation model of neuropathic pain before and following electrolytic lesion of the ACC.

Tuberoinfundibular peptide of 39 residues produces anxiolytic and antidepressant actions.

Tuberoinfundibular peptide of 39 residues (TIP39) potently activates the parathyroid hormone-2 receptor (PTH2-R). A group of neurons in the posterior thalamus and one in the lateral pons synthesize TIP39. TIP39 projections reach most areas of PTH2-R density, including many within the limbic system and hypothalamus.

Depletion of intracellular zinc from neurons by use of an extracellular chelator in vivo and in vitro.

The membrane-impermeable chelator CaEDTA was introduced extracellularly among neurons in vivo and in vitro for the purpose of chelating extracellular Zn(2+). Unexpectedly, this treatment caused histochemically reactive Zn(2+) in intracellular compartments to drop rapidly. The same general result was seen with intravesicular Zn(2+), which fell after CaEDTA infusion into the lateral ventricle of the brain, with perikaryal Zn(2+) in Purkinje neurons (in vivo) and with cortical neurons (in vitro).

Sex differences in the acquisition of a radial maze task in the CD-1 mouse.

The purpose of the present study was to investigate spatial processing performance in male and female CD-1 mice. A substantial literature supports the existence of significant sex differences in both human and rodent models of learning and memory. The nature of these differences is dependent upon the parameters of the task, species and strain of animal.

Catecholamine depletion by reserpine blocks the anxiolytic actions of ethanol in the rat.

Neurochemical investigations of the anti-anxiety action of ethanol demonstrate that increased dopaminergic, noradrenergic, and serotonergic activity mediates the anxiolytic actions of ethanol. Results of studies with animals and human beings also confirm an involvement of the sympathetic nervous system in the behavioral actions of ethanol. Because enhanced sympathetic activity increases the release of norepinephrine from sympathetic terminals, the interruption of normal sympathetic activity might disrupt the anxiolytic action of ethanol.

Enhanced formalin nociceptive responses following L5 nerve ligation in the rat reveals neuropathy-induced inflammatory hyperalgesia.

The development of mechanical and thermal hypersensitivity following peripheral nerve injury is well known and a great deal of research has been directed towards understanding the mechanisms underlying these phenomena. However, there has been very little research examining if hypersensitivity to an inflammatory condition following nerve injury also develops. Therefore, the purpose of the present study was to determine if hypersensitivity to an inflammatory condition produced in the formalin test develops following ligation of the L5 spinal nerve.