Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:56-45-1 (serine)
 65,846 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for treatment of pain, inflammation, and other central nervous system disorders. However, the FAAH inhibitors reported to date lack drug-like pharmacokinetic properties and/or selectivity. Herein we describe piperidine/piperazine ureas represented by N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750) and N-phenyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide (PF-622) as a novel mechanistic class of FAAH inhibitors. PF-750 and PF-622 show higher in vitro potencies than previously established classes of FAAH inhibitors. Rather unexpectedly based on the high chemical stability of the urea functional group, PF-750 and PF-622 were found to inhibit FAAH in a time-dependent manner by covalently modifying the enzyme's active site serine nucleophile. Activity-based proteomic profiling revealed that PF-750 and PF-622 were completely selective for FAAH relative to other mammalian serine hydrolases. We hypothesize that this remarkable specificity derives, at least in part, from FAAH's special ability to function as a C(O)-N bond hydrolase, which distinguishes it from the vast majority of metabolic serine hydrolases in mammals that are restricted to hydrolyzing esters and/or thioesters. The piperidine/piperazine urea may thus represent a privileged chemical scaffold for the synthesis of FAAH inhibitors that display an unprecedented combination of potency and selectivity for use as potential analgesic and anxiolytic/antidepressant agents.
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PMID:Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. 1794 10

In recent studies one serine residue (Ser-346) within the protein-kinase-A (R-E-S-R) consensus sequence of the GlyRalpha3 intracellular loop has proven to be an essential target for prostaglandin-E(2)-mediated phosphorylation, which further modulates spinal nociceptive transmission and central inflammatory pain sensitization. In the present study we investigated the effect of Ser-346 phosphorylation and Ser-346 mutation on receptor kinetics and function using whole-cell patch-clamp recordings in transfected HEK 293 T cells. We compared biophysical properties of wild type GlyRalpha3 and two site-directed mutants, where Ser-346 was replaced by alanine or aspartate, in the absence and presence of prostaglandin-E(2). The mutation to alanine was accompanied by significantly altered dose-response and desensitization properties. Mutation to aspartate had only minor effects on receptor kinetics and function. Phosphorylation of Ser-346 slowed desensitization and decreased glycinergic currents in GlyRalpha3/mEP2 transfected cells. In addition, we demonstrated that prostaglandin-E(2) also had an effect on the GlyRalpha2 subunit. Exposure to prostaglandin-E(2) decreased the maximum peak current amplitude of glycinergic currents in GlyRalpha2/mEP2 transfected cells in the same manner as phosphorylation of the GlyRalpha3 subunit. It led to a significant increase of the desensitization time constants and thus significantly affected the desensitization behaviour. These results indicate that the GlyRalpha2 and the GlyRalpha3 subunits act as important subunits for the modulation of glycine receptor kinetics and function.
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PMID:Kinetics and functional characterization of the glycine receptor alpha2 and alpha3 subunit. 1799 21

A Malaysian family with congenital insensitivity to pain with anhydrosis was diagnosed based on clinical symptoms of chronic ulcers, joint deformities, malunited fractures, anhydrosis, and learning disabilities. We detected a compound heterozygous mutation in exon 16: V709L from the mother and G718S from the father. Two novel mutations were identified: at amino acid 709, a change of G to C at nucleotide 2209 (approximately 2209G to C) causing a valine to leucine substitution (V709L), and at amino acid 718, a change of G to A at nucleotide 2236 (approximately 2236G to A) causing a glycine to serine substitution (G718S). Polymorphisms identified were at nucleotides approximately 2113G to C and approximately 2176T to C.
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PMID:Congenital insensitivity to pain with anhydrosis in a Malaysian family: a genetic analysis. 1816 86

The present study aims to investigate changes of spinal cord AMPA receptor GluR1 and its phosphorylation in inflammatory and neuropathic pain. Complete Freund's adjuvant (CFA) injection into the hind paw produced inflammatory thermal hyperalgesia that was assessed by decreased response latency to radiant heat; spinal nerve ligation (SNL) was used to induce mechanical allodynia that was evaluated with von Frey hairs. By method of Western blot, expression of GluR1 (the main subunit of the AMPA receptor) and its phosphorylated forms at serine 845 (pGluR1-Ser845) and at serine 831 (pGluR1-Ser831) in the spinal dorsal horn was observed. It was found that the expression of pGluR1-Ser845 and pGluR1-Ser831 increased significantly at 1 h after CFA injection, reached peak at 4 h and returned to the normal control level at 24 h, while no significant change was detected in GluR1 itself. In contrast, neither GluR1 nor pGluR1 showed any significant change in rats following SNL. These results suggest that phosphorylated GluR1 (pGluR1-Ser845 and pGluR1-Ser831) might play a role in the induction of inflammatory but not neuropathic pain.
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PMID:Role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit GluR1 in spinal dorsal horn in inflammatory nociception and neuropathic nociception in rat. 1828 17

The sensory neuron-specific sodium channel Na(v)1.8 and p38 mitogen-activated protein kinase are potential therapeutic targets within nociceptive dorsal root ganglion (DRG) neurons in inflammatory, and possibly neuropathic, pain. Na(v)1.8 channels within nociceptive DRG neurons contribute most of the inward current underlying the depolarizing phase of action potentials. Nerve injury and inflammation of peripheral tissues cause p38 activation in DRG neurons, a process that may contribute to nociceptive neuron hyperexcitability, which is associated with pain. However, how substrates of activated p38 contribute to DRG neuron hyperexcitability is currently not well understood. We report here, for the first time, that Na(v)1.8 and p38 are colocalized in DRG neurons, that Na(v)1.8 within DRG neurons is a substrate for p38, and that direct phosphorylation of the Na(v)1.8 channel by p38 regulates its function in these neurons. We show that direct phosphorylation of Na(v)1.8 at two p38 phospho-acceptor serine residues on the L1 loop (S551 and S556) causes an increase in Na(v)1.8 current density that is not accompanied by changes in gating properties of the channel. Our study suggests a mechanism by which activated p38 contributes to inflammatory, and possibly neuropathic, pain through a p38-mediated increase of Na(v)1.8 current density.
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PMID:Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. 1835 22

Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl)amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4-benzyloxy-3,5-dimethoxy-N-[1-(dimethylaminocyclopently)-methyl]benzamide (ORG25543) and (O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-L-serine) (ALX1393), or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor alpha3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.
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PMID:Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. 1844 67

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (GI) function; these effects are mediated through G protein transduction. Candidate genetic variations in ADR-SER were significantly associated with somatic scores in irritable bowel syndrome (IBS) and gastric emptying but not small bowel or colonic transit. Our aim was to assess whether candidate ADR-SER genes are associated with motor and sensory GI functions in IBS and subgroups on the basis of bowel dysfunction. In 122 patients with IBS and 39 healthy controls, we assessed gastrointestinal somatic symptoms and affect by validated questionnaires. We measured: gastric volume (GV), maximum tolerated volume, rectal compliance, sensation thresholds and ratings, and genetic variations including alpha2A (C-1291G), alpha2C (Del 332-325), GNbeta3 (C825T), and 5-HTTLPR. Demographics and genotype distributions were similar in the patients with IBS subgrouped on bowel function. There were significant associations between 5-HTTLPR SS genotype and absence of IBS symptoms and between 5-HTTLPR LS/SS genotype and increased rectal compliance and increased pain ratings, particularly at 12 and 24 mmHg distensions. GNbeta3 was associated only with fasting GV; we did not detect associations between alpha2A genotype and the gastrointestinal sensory or motor functions tested. We concluded that 5-HTTLPR LS/SS genotype is associated with both increased pain sensation and increased rectal compliance though the latter effect is unlikely to contribute to increased pain sensation ratings with LS/SS genotype. The data suggest the hypotheses that the endophenotype of visceral hypersensitivity in IBS may be partly related to genetic factors, and the association of GNbeta3 with fasting GV may explain, in part, the reported association of GNbeta3 with dyspepsia.
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PMID:Candidate genes and sensory functions in health and irritable bowel syndrome. 1851 40

Proteinase-activated receptors (PARs) are G-protein-coupled receptors that are activated by the proteolytic cleavage of their N-terminal domain. The new N-terminal sequence that is exposed by proteolysis acts as a tethered ligand, which binds to and activates the receptor. PAR-2 is highly expressed in the gastrointestinal tract, where it is found in endothelial cells, colonic myocytes, enterocytes (both on basolateral and apical membranes), enteric neurons, terminals of mesenteric afferent nerves and immune cells. In the gastrointestinal tract, PAR-2 may be activated by tryptase from mast cells but also by luminal proteases such as trypsin and possibly bacterial proteases. In addition to effects on motility, ion and mucus secretion, activation of PAR-2 receptors from luminal affects visceral pain. In rats, the intracolonic infusion of PAR-2 agonists (SLIGRL, trypsin) initiates a delayed hypersensitivity to colonic distension. These effects are locally mediated since they are not observed for systemic administration. Interestingly, such pronociceptive effect of local activation of PAR-2 is associated with increased colonic paracellular permeability. Blockade of such increase in permeability, prevents the occurrence of hypersensitivity to rectal distension suggesting that activation of the local immune system by luminal toxins and antigens is responsible for the sensitization of primary afferent terminals to mechanical stimuli. Consequently, blockade of PAR-2 receptors at the periphery and/or inhibition of colonic luminal protease activity may be new interesting targets for the treatment of gut hypersensitivity and IBS. A recent study has evidenced that stool supernatants from diarrhea predominant IBS patients have a high level of serine-protease activity that increases permeability and colonic hypersensitivity when infused intra-colonically in mice, and these effects are linked to activation of PAR-2 receptors. These data support a possible role of luminal proteases in the pathogenesis of IBS and give a rationale to target PARs and more specifically PAR-2 as future treatment of IBS.
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PMID:Protease activated receptor 2: a new target for IBS treatment. 1892 48

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (gastrointestinal, GI) sensorimotor functions. We aimed to determine whether candidate ADR-SER genes affect GI responses to low dose clonidine (CLO) in humans. Forty healthy and 120 irritable bowel syndrome (IBS) participants received CLO, 0.1 mg or 0.15 mg b.i.d., for 6 days. At baseline and post-CLO, we measured: gastric volume (GV); satiation volume; rectal compliance, sensation thresholds and ratings with distensions. Genetic variations tested were: alpha2A (C-1291G), alpha2C (Del 322-325), GNbeta3 (C825T) and solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) (serotonin transporter linked polymorphic region). CLO reduced volume to satiation (P = 0.002), postprandial GV (P < 0.001), sensation threshold for pain (<0.001); CLO increased rectal compliance (P = 0.024). There were significant associations between post-CLO responses and gene variations for DeltaGV (alpha2A and SLC6A4), rectal sensation of gas (alpha2A, GNbeta3), urgency (alpha2A); and pain (GNbeta3 and SLC6A4); and rectal compliance (SLC6A4). alpha2A, GNbeta3 and SLC6A4 genotypes significantly modify responses to CLO on sensory and motor GI functions in health and IBS.
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PMID:Pharmacogenetics of low dose clonidine in irritable bowel syndrome. 1930 15

Inflammation is a major characteristic of envenomation by snakes from viperine and crotaline species. Bothrops asper snake venom elicits, among other alterations, a pronounced inflammatory response at the site of injection both in humans and experimental animals. This review describes the current status of our understanding of the inflammatory reaction, including pain, triggered by Bothrops asper venom. The experimental studies on the action of this venom as well as the complex network of chemical mediators involved are summarized. Moreover, aspects of the molecular mechanisms orchestrating this important response to envenomation by Bothrops asper are presented. Considering that isolated toxins are relevant tools for understanding the actions of the whole venom, studies dealing with the mechanisms of inflammatory and nociceptive properties of phospholipases A(2), a metalloproteinase and serine-proteases isolated from Bothrops asper venom are also described.
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PMID:Inflammation induced by Bothrops asper venom. 1932 21


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