Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor.

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.

Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.

Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain.

Several studies have implicated a potential role for histamine H(3) receptors in pain processing, although the data are somewhat conflicting. In the present study we investigated the effects of the novel potent and highly selective H(3) receptor antagonists GSK189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride) and GSK334429 (1-(1-methylethyl)-4-([1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl]carbonyl)hexahydro-1H-1,4-diazepine) in two rat models of neuropathic pain, namely the chronic constriction injury (CCI) model and the varicella-zoster virus (VZV) model. Both GSK189254 (0.

Localisation and modulation of prostanoid receptors EP1 and EP4 in the rat chronic constriction injury model of neuropathic pain.

Immunohistochemistry was used to examine the expression of prostaglandin E(2) receptors EP1 and EP4 in sciatic nerves from the rat chronic constriction injury (CCI) model of neuropathic pain. At 21 days post-surgery the CCI rats had developed mechanical hyperalgesia on the operated side, and quantitative image analysis showed a highly significant doubling of the area occupied by EP1- and EP4-positive pixels in sections from CCI nerves when compared to sham-operated controls. Co-localisation studies with the marker ED1 revealed that 73% of the EP1-positive cells and 54% of the EP4-positive cells in the injured nerves represented infiltrating macrophages.

Investigation into the role of P2X(3)/P2X(2/3) receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study.

1. Two P2X(3)/P2X(2/3) receptor antagonists with different potencies were profiled electrophysiologically in a rat model of nerve injury. 2.

Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of nerve injury: a time-course study.

Background: Recent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for production of prostanoids, which may sensitise sensory neurones via the EP1 receptor. We have recently reported that while macrophages infiltrate injured nerves within days of injury, they express increased Cox-2-immunoreactivity (Cox-2-IR) from 2 to 3 weeks after injury.

GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain.

Nitric oxide (NO), synthesised by different isoforms of nitric oxide synthase (NOS), has been linked with the development and maintenance of nociception. We studied the role of the inducible isoform, iNOS, in two different rat pain models with an inflammatory component. iNOS was immunohistochemically detected locally in the paw 6h after Freund's Complete Adjuvant (FCA) injection, showing a plateau at 24-72 h and falling slowly in the following weeks.

Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and anti-nociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain.

The objective of this investigation was to characterise the pharmacokinetic-pharmacodynamic correlation of adenosine A1 receptor partial agonists in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 8-methylamino-N6-cyclopentyl-adenosine (MCPA; 10 mg/kg) and 2'deoxyribose-N6-cyclopentyl-adenosine (2'dCPA; 20 mg/kg), the time course of the effect on the mechanical paw pressure threshold was determined in conjunction with plasma concentrations. Population pharmacokinetic/pharmacodynamic analysis was applied to derive individual concentration-effect relationships.

The cyclooxygenase-2 inhibitor GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine] is effective in animal models of neuropathic pain and central sensitization.

The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.

Population pharmacokinetic-pharmacodynamic modelling of the anti-hyperalgesic effect of 5'deoxy-N6-cylopentyladenosine in the mononeuropathic rat.

The objective of this investigation was to characterise the pharmacokinetic-pharmacodynamic correlation of 5'-deoxy-N6-cyclopentyl-adenosine (5'dCPA) in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 5'dCPA (0.30 or 0.