ABSTRACT
Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.
Subject(s)
Amides/pharmacology , Benzothiazoles/pharmacology , Pain/drug therapy , TRPV Cation Channels/antagonists & inhibitors , Amides/administration & dosage , Amides/chemistry , Animals , Benzothiazoles/administration & dosage , Benzothiazoles/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Inflammation/drug therapy , Molecular Structure , Rats , Recombinant Proteins/antagonists & inhibitors , Solubility , Structure-Activity RelationshipABSTRACT
PURPOSE: This study was designed to examine the effect of Freund's complete adjuvant (FCA)-induced inflammation on liver P450 expression and activities in the first 7 days that followed a single FCA injection in the rat hindpaw. METHODS: Rats were humanely sacrificed at regular time points, plasma and liver samples were collected, liver mRNA extracted, and liver microsomes prepared. RESULTS: FCA injection led to the development of an acute inflammatory response evidenced by paw edema and increased alpha-1-acid glycoprotein (AGP) and total-nitrite (NOx) plasma concentrations. Plasma IL-6 levels were significantly higher in FCA-treated rats than in controls at 8 h post-FCA. Within 24 h, these changes were accompanied by a rapid decrease in total P450 contents in FCA-treated rat liver and the selective downregulation of specific CYP isoforms, as illustrated by decreased mRNA levels (CYP2B, CYP2CI1, CYP3A1, and CYP2E1), protein contents (CYP2B, CYP2C11, and CYP2E1) or catalytic activities (CYP2C6, CYP2C11, and CYP2E1). CYP3A1 mRNA levels were severely decreased by FCA administration, whereas CYP3A2 mRNA and protein levels remained unchanged. CONCLUSIONS: These early biochemical and metabolic modifications may have pharmacokinetic and pharmacodynamic consequences when hepatically cleared drugs are administered to FCA-treated rats, especially within the first 24-72 h post-FCA.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/biosynthesis , Disease Models, Animal , Down-Regulation/physiology , Liver/enzymology , Liver/pathology , Pain/enzymology , Animals , Cytochrome P-450 Enzyme System/metabolism , Freund's Adjuvant/administration & dosage , Inflammation/chemically induced , Inflammation/enzymology , Inflammation/genetics , Inflammation Mediators/administration & dosage , Male , Pain/genetics , Rats , Rats, Sprague-DawleyABSTRACT
The sensory neuron-specific G protein coupled receptors (SNSRs) have been described as a family of receptors whose expression in small diameter sensory neurons in the trigeminal and dorsal root ganglia suggests an implication in nociception. To date, the physiological function(s) of SNSRs remain unknown. Hence, the aim of the present study was to determine the effects of rat SNSR1 activation on nociception in rats. The pharmacological characterization of rat SNSR1 was initially performed in vitro to identify a specific ligand, which could be used subsequently in the rat for physiological testing. Among all ligands tested, gamma2-MSH was the most potent at activating rat SNSR1. Structure-activity relationship studies revealed that the active moiety recognized by rat SNSR1 was the C-terminal part of gamma2-MSH. The radiolabeled C-terminal part of gamma2-MSH, gamma2-MSH-6-12, bound with high affinity to membranes derived from rat skin and spinal cord, demonstrating the presence of receptor protein at both the proximal and distal terminals of dorsal root ganglia. To investigate the physiological role of SNSR, specific ligands to rat SNSR1 were tested in behavioral assays of pain sensitivity in rats. Selective rat SNSR1 agonists produced spontaneous pain behavior, enhanced heat and mechanical sensitivity when injected intradermally, and heat hypersensitivity when injected centrally, consistent with the localization of rat SNSR1 protein at central and peripheral sites. Together, these results clearly indicate that the SNSR1 plays a role in nociception and may provide novel therapeutic opportunities for analgesia.
Subject(s)
Melanocyte-Stimulating Hormones/metabolism , Neurons, Afferent/metabolism , Receptors, Cell Surface/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Behavior, Animal , Humans , Pain/metabolism , Rats , Receptors, Cell Surface/agonistsABSTRACT
Using a rabbit model of methicillin-resistant Staphylococcus aureus knee-prosthesis infection, we studied the efficacy of teicoplanin cement alone or in combination with systemic intramuscular (i.m.) injections of teicoplanin. Seven days after infection, surgical debridement and removal of the infected prostheses were performed, and five rabbits were randomly assigned to one of five different treatment groups: untreated controls, prosthesis replacement by drug-free cement spacer, prosthesis replacement by teicoplanin-loaded cement spacer (1.2 g of teicoplanin/40 g of cement), i.m. injections of teicoplanin (20 mg/kg of body weight, twice a day for 7 days), or systemic antibiotic treatment combined with teicoplanin-loaded spacers. The most effective regimen combined systemic teicoplanin and antibiotic spacers.
