The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 2008
Comparative StudyComparison of the novel subtype-selective GABAA receptor-positive allosteric modulator NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with diazepam, zolpidem, bretazenil, and gaboxadol in rat models of inflammatory and neuropathic pain.
Spinal administration of GABA(A) receptor modulators, such as the benzodiazepine drug diazepam, partially alleviates neuropathic hypersensitivity that manifests as spontaneous pain, allodynia, and hyperalgesia. However, benzodiazepines are hindered by sedative impairments and other side effect issues occurring mainly as a consequence of binding to GABA(A) receptors containing the alpha(1) subunit. Here, we report on the novel subtype-selective GABA(A) receptor-positive modulator NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], which possesses a functional efficacy selectivity profile of alpha(5) > alpha(3) > alpha(2) > alpha(1) at GABA(A) alpha subunit-containing receptors. ⋯ In contrast, putative antinociception associated with administration of either diazepam, zolpidem, or gaboxadol only occurred at doses producing intolerable side effects, whereas bretazenil was completely inactive despite minor influences on motoric function. In electrophysiological studies, NS11394 selectively attenuated spinal nociceptive reflexes and C-fiber-mediated wind-up in vitro pointing to involvement of a spinal site of action. The robust therapeutic window seen with NS11394 in animals suggests that compounds with this in vitro selectivity profile could have potential benefit in clinical treatment of pain in humans.
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J. Pharmacol. Exp. Ther. · Dec 2008
Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity.
P38alpha is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38alpha and p38beta enzymatic activity, with IC(50) values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. ⋯ In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.
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J. Pharmacol. Exp. Ther. · Dec 2008
Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist.
Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N'-propylaminosulfonamide], is a new dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. ⋯ In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage (renal vascular hypertrophy and structural injury). In conclusion, macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.