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Concept: Receptor antagonist


Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect.

Concepts: Effectiveness, Menopause, Receptor, Receptor antagonist


The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.

Concepts: Pharmacology, Signal transduction, Receptor antagonist, Dopamine receptor, Agonist, Schizophrenia, Dopamine receptor D2, Adenosine A2A receptor


Quorum sensing (QS) is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in V. cholerae have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate V. cholerae QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global V. cholerae QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in Vibrio species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.

Concepts: Bacteria, Microbiology, Receptor antagonist, Biofilm, Vibrio cholerae, Bioluminescence, Vibrio


Accumulated evidence has suggested that potentiation of cortical GABAergic inhibitory neurotransmission may be a key mechanism in the treatment of schizophrenia. However, the downstream molecular mechanisms related to GABA potentiation remain unexplored. Recent studies have suggested that dopamine D2 receptor antagonists, which are used in the clinical treatment of schizophrenia, modulate protein kinase B (Akt)/glycogen synthase kinase (GSK)-3 signaling. Here we report that activation of GABAB receptors significantly inhibits Akt/GSK-3 signaling in a beta-arrestin-dependent pathway. Agonist stimulation of GABAB receptors enhances the phosphorylation of Akt (Thr-308) and enhances the phosphorylation of GSK-3alpha (Ser-21)/beta (Ser-9) in both HEK-293T cells expressing GABAB receptors and rat hippocampal slices. Furthermore, knocking down the expression of beta-arrestin2 using siRNA abolishes the GABAB receptor-mediated modulation of GSK-3 signaling. Our data may help to identify potentially novel targets through which GABAB receptor agents may exert therapeutic effects in the treatment of schizophrenia.

Concepts: Signal transduction, Receptor, Receptor antagonist, Dopamine receptor, Neurotransmitter, Schizophrenia, Dopamine receptor D2, GABAB receptor


Dopaminergic neurons of the ventral tegmental area are important components of brain pathways related to addiction. Prolonged exposure of these neurons to moderate concentrations of dopamine (DA) decreases their sensitivity to inhibition by DA, a process called DA-inhibition reversal (DIR). DIR is mediated by phospholipase C and conventional subtype of protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of 5-HT(2) or neurotensin receptors. In the present study, we further characterized this phenomenon by use of extracellular recordings in brain slices to examine whether DIR is linked to G protein-coupled receptor kinase-2 (GRK2) or dynamin by assessing DIR in the presence of antagonists of these enzymes. DIR was blocked by β-ARK1 inhibitor, which inhibits GRK2, and by dynasore, which blocks dynamin. Reversal of inhibition by D2 agonist quinpirole was produced by serotonin (50 µM) and by neurotensin (5-10 nM). Serotonin-induced or neurotensin-induced reversal was blocked by β-ARK1 inhibitor, dynasore, or cPKC antagonist 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile (Gö6976). This further characterization of DIR indicates that cPKC, GRK2, and dynamin play important roles in the desensitization of D2 receptors. As drugs of abuse produce persistent increases in DA concentration in the ventral tegmental area, reduction of D2 receptor sensitivity as a result of drug abuse may be a critical factor in the processes of addiction.

Concepts: Signal transduction, Enzyme inhibitor, Receptor antagonist, Dopamine receptor, Serotonin, Drug addiction, Addiction, Dopamine


The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CL(tot)/F) and renal clearance (CL®) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CL(tot)/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CL(tot)/F of fexofenadine enantiomers, whereas the stereoselectivity in the CL® persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1)-mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses.

Concepts: Pharmacology, Human, Receptor, Ligand, Histamine, Receptor antagonist, Inverse agonist, Histamine H1 receptor


Purinergic signaling contributes significantly to pain mechanisms, and the nociceptor-specific P2X3 ATP receptor channel is considered a target in pain therapeutics. Recent evidence for co-expression of metabotropic P2Y receptors with P2X3 suggests that ATP release triggers the activation of both ionotropic and metabotropic purinoceptors, with strong potential for functional interaction. Modulation of native P2X3 function by P2Y receptor activation was investigated in rat dorsal root ganglia (DRG) neurons using whole-cell patch-clamp recordings. Application of the selective P2Y receptor agonist UTP decreased peak amplitudes of α,β-meATP-evoked homomeric P2X3-mediated currents, but had no effect on heteromeric P2X2/3-mediated currents. Treatment with phospholipase C (PLC) inhibitor U73122 significantly reversed P2X3 current inhibition induced by UTP-sensitive P2Y receptor activation. We previously reported the modulation of P2X receptors by phospholipids in DRG neurons and injection of exogenous phosphatidylinositol-4,5-bisphosphate (PIP2) fully reverses UTP-mediated regulation of P2X3 channel activity. Pharmacological as well as functional screening of P2Y receptor subtypes indicates the predominant involvement of P2Y2 receptor in P2X3 inhibition and immunolocalization confirms a significant cellular co-expression of P2X3 and P2Y2 in rat DRG neurons. In summary, the function of P2X3 ATP receptor can be inhibited by P2Y2-mediated depletion of PIP2. We propose that expression of P2Y2 purinoceptor in nociceptive sensory neurons provides an homeostatic mechanism to prevent excessive ATP signaling through P2X3 receptor channels.

Concepts: Nervous system, Signal transduction, Receptor, Action potential, Sensory system, Receptor antagonist, Serotonin, Inverse agonist


Thrombin activates platelets through protease activated receptors (PARs). Mouse platelets express PAR3 and PAR4. PAR3 does not signal in platelets. However, PAR4 is a relatively poor thrombin substrate and requires PAR3 as a cofactor at low thrombin concentrations. In this study we show that PAR3 also regulates PAR4 signaling. In response to thrombin (30-100 nM) or PAR4 activating peptide (AYPGKF), platelets from PAR3(-/-) mice had increased G(q) signaling compared to wild type mice as demonstrated by a 1.6-fold increase in the maximum intracellular calcium (Ca(2+)) mobilization, an increase in phosphorylation level of protein kinase C (PKC) substrates, and a 2-fold increase of Ca(2+) release from intracellular stores. Moreover, platelets from heterozygous mice (PAR3(+/-)) had an intermediate increase in maximum Ca(2+) mobilization. Treatment of PAR3(-/-) mice platelets with P2Y(12) antagonist (2MeSAMP) did not affect Ca(2+) mobilization from PAR4 in response to thrombin or AYPGKF. The activation of RhoA-GTP downstream G(12/13) signaling in response to thrombin was not significantly different between wild type and PAR3(-/-) mice. Since PAR3 influenced PAR4 signaling independent of agonist, we examined the direct interaction between PAR3 and PAR4 with bioluminescence resonance energy transfer (BRET). PAR3 and PAR4 form constitutive homodimers and heterodimers. In summary, our results demonstrate that in addition to enhancing PAR4 activation at low thrombin concentrations, PAR3 negatively regulates PAR4-mediated maximum Ca(2+) mobilization and PKC activation in mouse platelets by physical interaction.

Concepts: Signal transduction, Enzyme, Cell biology, Receptor, Protein kinase, Receptor antagonist, Protein kinase C, Protease-activated receptor


BACKGROUND: Brazilin, isolated from the heartwood of Caesalpinia sappan L., has been shown to possess multiple pharmacological properties. METHODS: In this study, platelet aggregation, flow cytometry, immunoblotting analysis, and electron spin resonance (ESR) spectrometry were used to investigate the effects of brazilin on platelet activation ex vivo. Moreover, fluorescein sodium-induced platelet thrombi of mesenteric microvessels was also used in in vivo study. RESULTS: We demonstrated that relatively low concentrations of brazilin (1 to 10 muM) potentiated platelet aggregation induced by collagen (0.1 mug/ml) in washed human platelets. Higher concentrations of brazilin (20 to 50 muM) directly triggered platelet aggregation. Brazilin-mediated platelet aggregation was slightly inhibited by ATP (an antagonist of ADP). It was not inhibited by yohimbine (an antagonist of epinephrine), by SCH79797 (an antagonist of thrombin protease-activated receptor [PAR] 1), or by tcY-NH2 (an antagonist of PAR 4). Brazilin did not significantly affect FITC-triflavin binding to the integrin alphaIIbbeta3 in platelet suspensions. Pretreatment of the platelets with caffeic acid phenethyl ester (an antagonist of collagen receptors) or JAQ1 and Sam.Q4 monoclonal antibodies raised against collagen receptor glycoprotein VI and integrin alpha2beta1, respectively, abolished platelet aggregation stimulated by collagen or brazilin. The immunoblotting analysis showed that brazilin stimulated the phosphorylation of phospholipase C (PLC)gamma2 and Lyn, which were significantly attenuated in the presence of JAQ1 and Sam.Q4. In addition, brazilin did not significantly trigger hydroxyl radical formation in ESR analysis. An in vivo mouse study showed that brazilin treatment (2 and 4 mg/kg) significantly shortened the occlusion time for platelet plug formation in mesenteric venules. CONCLUSION: To the best of our knowledge, this study provides the first evidence that brazilin acts a novel collagen receptor agonist. Brazilin is a plant-based natural product, may offer therapeutic potential as intended anti-thrombotic agents for targeting of collagen receptors or to be used a useful tool for the study of detailed mechanisms in collagen receptors-mediated platelet activation.

Concepts: Signal transduction, Cell biology, In vivo, Platelet, Receptor antagonist, Serotonin, Inverse agonist, GPVI


Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H(+)] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.

Concepts: Pancreas, Stomach, Receptor antagonist, Cannabinoid receptor, Digestion, Gastric acid, Somatostatin, HU-210