MH_dev_213

P13726 REA and factor VIIa as therapeutic targets in disorders of hemostasis . For hemophilia patients with inhibitors against FVIII or FIX , the development of recombinant factor VIIa ( DB00036 MEN ) raises the possibility of a therapeutic alternative whose availability and convenience of treatment are comparable to those of FVIII or FIX . In support of this new concept for the treatment of bleeding episodes , pharmacological doses of FVIIa have been shown to induce hemostasis . Pharmacological doses of DB00036 MEN enhance thrombin generation on thrombin-activated platelets , thereby facilitating the formation of strong , well-structured fibrin plugs resistant to premature proteolysis . Modified DB00036 MEN molecules with a stronger hemostatic potential have been produced . Inhibition of the FVII-TF-dependent pathway ( P10646 REA and rFVIIai ) has been tried in attempts to prevent thrombosis , with promising results in animal models so far not confirmed in clinical trials .

Distribution of polyamines and their biosynthetic enzymes in intestinal adaptation . P11926 REA ( ODC ) and the polyamines have been shown to be important for growth processes in the intestinal mucosa . The highest activity of ODC is found in the differentiated , nonproliferating villus-tip cells rather than in the rapidly proliferating undifferentiated crypt cells . During poststarvation refeeding and lactation , we now show that increases in ODC activity paralleled the time course of mucosal hyperplasia and thymidine incorporation . Increases in ODC ( threefold ) were similar in villus and crypt cells , and the villus-crypt gradient of decreasing ODC activity ( 40:1 ) was maintained . The activity of the other polyamine biosynthetic enzyme , S-adenosylmethionine decarboxylase ( P18827 REA ) , was highest in the crypt cells in the basal state and increased throughout the entire villus-crypt axis during refeeding and lactation , preserving a villus-crypt gradient opposite to that of ODC . During hyperplasia , all three polyamines increased . DB01917 MEN was highest in the villus-tip cells , paralleling ODC activity , whereas spermidine and spermine were highest in the crypt cells and paralleled the distribution of P18827 REA activity . Thus P18827 REA activity and spermidine and spermine content may play a more important role than ODC and putrescine in regulation of intestinal mucosal proliferation . It is also possible that the threefold increases in the low levels of ODC in the crypt cells are adequate to trigger cell proliferation , whereas the higher ODC levels in villus cells may represent an association with the differentiation of the enterocytes .

Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds . Using radioligand binding assays and post-mortem normal human brain tissue , we obtained equilibrium dissociation constants ( K ( d ) s ) for nine new antipsychotic drugs ( iloperidone , melperone , olanzapine , ORG 5222 , quetiapine , risperidone , sertindole , ziprasidone , and zotepine ) , one metabolite of a new drug ( 9 - OH-risperidone ) , and three older antipsychotics ( clozapine , haloperidol , and pimozide ) at nine different receptors ( alpha 1 - adrenergic , alpha 2 - adrenergic , dopamine D2 , histamine H1 , muscarinic , and serotonin P08908 REA , P28221 REA , 5 - Q13049 REA , and P28335 REA receptors ) . DB04946 SUB was the most potent drug at the two adrenergic receptors . ORG 5222 was the most potent drug at dopamine D2 and 5 - HT2c receptors , while ziprasidone was the most potent compound at three serotonergic receptors ( P08908 REA , P28221 REA , and 5 - Q13049 REA ) . At the remaining two receptors , olanzapine was the most potent drug at the histamine H1 receptor ( Kd = 0.087 nM ) ; clozapine at the muscarinic receptor ( Kd = 9 nM ) . Certain therapeutic and adverse effects , as well as certain drug interactions can be predicted from a drug ' s potency for blocking a specific receptor . These data can provide guidelines for the clinician in the choice of antipsychotic drug .

Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 REA ) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients , at 72 h post-challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2,5- dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell-like line ( XS52 ) , regarding its IL - 1beta production . Serotonin-positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0.01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 REA - positive cells were increased ( p < 0.001 for both ) in the eczematous skin . Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10 ( - 5 ) mol / l of DOI inhibited ( p < 0.01 ) the proliferation of nickel-stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 REA production . DB00215 MENMAX DB00215 MEN at 10 ( - 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .

P01308 REA - like growth factor-I as a promoting factor for cerebellar Purkinje cell development . In the mammalian CNS , the peptide hormone insulin-like growth factor-I ( P05019 REA ) is synthesized in a certain subset of neurons and , it has been suggested , serves as a local neurotrophic factor . A postnatal increase in the expression of P05019 REA and the type - 1 IGF receptors ( P12314 REA ) in the cerebellar cortex and its related brain regions indicates that developing cerebellar Purkinje cells ( PC ) may be an important target of P05019 REA . However , little is known about how P05019 REA influences PC development . Here we addressed this question , using a reduced environment of cerebellar neuron culture derived from perinatal mice . P05019 REA exogenously applied at a physiological concentration ( 10 nm ) greatly promoted the dendritic growth and survival of the PCs . By contrast , P05019 REA only slightly promoted the somatic growth and little affected the maturation of the electrophysiological excitability of the PCs . The closely related hormone insulin had weaker promoting effects than did P05019 REA . P05019 REA appeared to at least bind to P12314 REA and to up-regulate the signalling pathways involving the phosphoinositide 3 - kinase ( P19957 REA - K ) , mitogen-activated protein kinase ( MAPK ) , p38 kinase ( p38K ) , and an unknown signalling molecule ( s ) . These signalling pathways may be coupled to the individual aspects of PC development in different manners and this may explain the difference in effects of P05019 REA among these aspects . These findings suggest that P05019 REA serves as a promoting factor for PC development , particularly postnatal survival and dendritic growth .

[ 5 - hydroxytryptamine ( serotonin ) receptors - - nomenclature and classification of types and subtypes ] . 5 - HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes . At present 15 receptor subtypes of three groups has been recognized . The 5 - HT1 subfamily of receptors contains subtypes P08908 REA , P28222 REA , P28221 REA , P28566 REA , and P30939 REA ; activation of all of them results in the inhibition of adenylylcyclase . The subfamily of 5 - HT2 contains subtypes 5 - Q13049 REA , P41595 REA , and P28335 REA ; their activation leads to the stimulation of P98160 REA . Finally , subfamily of miscellaneous 5 - HT receptors contains subtypes 5 - Q9H205 REA , Q13639 REA , 5 - HT5 , P50406 REA , and P34969 REA ; some of them has been cloned , however , our knowledge on their function is still minimal . 5 - HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease . 5 - HT plays an important role in depression ; to cure this disease , drugs which increase levels of this neurotransmitter are used . A new drug group called Selective Serotonin Reuptake Inhibitors ( SSRI ) has been recently discovered . These drugs block the reuptake of 5 - HT into nerve endings . There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential .

Separation of peptides from detergents using ion mobility spectrometry . Mass spectrometry ( MS ) has dramatically evolved in the last two decades and has been the driving force of the spectacular expansion of proteomics during this period . However , the very poor compatibility of MS with detergents is still a technical obstacle in some studies , in particular on membrane proteins . Indeed , the high hydrophobicity of membrane proteins necessitates the use of detergents for their extraction and solubilization . Here , we address the analytical potential of high-field asymmetric waveform ion mobility spectrometry ( FAIMS ) for separating peptides from detergents . The study was focused on peptides from the human integral membrane protein P21926 REA . A tryptic peptide was mixed with the non-ionic detergents Triton X - 100 or beta-D-dodecyl maltoside ( DDM ) as well as with the ionic detergents sodium dodecyl sulfate ( SDS ) or sodium DB03619 ( P18827 REA ) . Although electrospray ionization ( P19957 REA ) alone led to a total suppression of the peptide ion signal on mass spectra with only detection of the detergents , use of FAIMS allowed separation and clear identification of the peptide with any of the detergents studied . The detection and identification of the target compound in the presence of an excess of detergents are then feasible . FAIMS should prove especially useful in the structural and proteomic analysis of membrane proteins .

P00505 REA from rat heart is phosphorylated on Tyr 19 in response to insulin stimulation . The cytosolic fatty acid-binding protein from rat heart ( P05413 REA , M ( r ) 15,000 ) as well as FABP from mouse adipocytes ( P15090 REA , 62 % homologous with P05413 REA ) contain a recognition sequence for protein tyrosine kinases , DB00174 - DB00120 - DB00128 MEN - DB00128 MEN - Tyr 19 . P15090 REA has been shown by others to be partly phosphorylated on Tyr 19 , thus encouraging experiments designed to search for phosphotyrosine in P05413 REA . For this purpose isolated cardiac myocytes were incubated with [ 32P ] orthophosphate and analyzed by two-dimensional gel electrophoresis . A 15 kDa phosphoprotein present in the cytosolic protein fraction was specifically precipitated by a polyclonal antibody against rat heart FABP . Characterization of the phosphorylated FABP was facilitated by the development of an immunoaffinity purification procedure capable of isolating more than 200 micrograms FABP from four rat hearts in one step . Phosphoamino acid analysis and radiosequencing of the major tryptic phosphopeptide from immunopurified FABP revealed Tyr 19 as the phosphorylated amino acid . Stimulation of cardiac myocytes with insulin in the presence of tyrosine phosphatase inhibitors led to a several-fold increase in the amount of phosphorylated FABP compared with a nearly undetectable level found without insulin stimulation , indicating that FABP may be a substrate for the insulin receptor tyrosine kinase . Phosphorylated FABP constitutes only a minor fraction compared to the large pool of FABP in the cardiac myocyte , thus obscuring the significance of this modification . However , as the phosphorylated Tyr 19 residue is positioned within a helix-turn-helix-related domain of FABP , this modification may modulate a hitherto unknown DNA binding activity of FABP . A hypothesis is discussed in which phosphorylated FABP serves as a signalling molecule in the insulin signal transduction cascade .

Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 REA receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 REA , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 REA receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol-specific phospholipase C ( P98160 REA ) and release of Ca2 + from internal stores , but this activation was not related to P35354 REA mRNA expression . Similarly , P19957 REA kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine-specific P98160 REA interfered with P35354 REA and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 REA receptors and protein kinase C , an essential part of 5 - HT-mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester-induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 REA or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT-mediated mRNA induction . P35354 REA mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 + - dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 + - sensitive posttranscriptional steps . Activation of the Gq-coupled 5 - Q13049 REA receptor thus leads to the expression of the early response genes P35354 REA and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .

Activation of the JAK - P35610 pathway is necessary for desensitization of 5 - Q13049 REA receptor-stimulated phospholipase C signalling by olanzapine , clozapine and MDL 100907 . We have previously demonstrated that olanzapine-induced desensitization of 5 - Q13049 REA receptor-stimulated phospholipase C ( P98160 REA ) activity is associated with increases in P49802 REA protein levels both in vivo and in cells in culture , and the increase in P49802 REA is dependent on activation of the JAK - P35610 pathway in cells in culture . In the present study , we found that desensitization of 5 - Q13049 REA receptor-stimulated P98160 REA activity induced by olanzapine is dependent on activation of the JAK - P35610 pathway . Similar to olanzapine , clozapine-induced desensitization of 5 - Q13049 REA receptor signalling is accompanied by increases in P49802 REA and activation of O60674 REA . Treatment with the selective 5 - Q13049 REA receptor antagonist MDL 100907 also increased P49802 REA protein levels and O60674 REA activation . Using a O60674 REA inhibitor AG490 , we found that clozapine and MDL 100907 - induced increases in P49802 REA are dependent on activation of the JAK - P35610 pathway . Olanzapine , clozapine , and MDL 100907 treatment increased mRNA levels of P49802 REA . Using a chromatin immunoprecipitation assay we found P40763 REA binding to the putative P49802 REA promoter region . Taken together , olanzapine-induced activation of the JAK - P35610 pathway , and P40763 REA binding to the P49802 REA gene could underlie the increase in P49802 REA mRNA which could subsequently increase protein expression . Furthermore , the increase in P49802 REA protein could play a role in the desensitization of 5 - Q13049 REA receptor signalling by terminating the activated Galphaq / 11 proteins more rapidly . Overall , our data suggest that the complete desensitization of 5 - Q13049 REA receptor-stimulated P98160 REA activity by olanzapine , clozapine and MDL 100907 requires activation of the JAK - P35610 pathway , which in turn increases P49802 REA expression probably by direct transcriptional activity of P40763 REA .

Production of prostaglandins in transgenic Arabidopsis thaliana . Plants do not naturally produce the very-long-chain polyunsaturated fatty acids that are the precursors of prostaglandins , but in previous studies Arabidopsis thaliana had been transformed sequentially with genes encoding a Δ ( 9 ) - elongase and a Δ (8 ) - desaturase to produce dihomo-γ-linolenic acid ( DB00154 MEN ) and eicosatetraenoic acid ( P25101 REA ) , and subsequently with a gene encoding a Δ ( 5 ) - desaturase to produce arachidonic acid ( AA ) and eicosapentaenoic acid ( EPA ) . Transformation of A . thaliana with the first two genes consolidated on a single binary vector yielded transformants producing high levels of DB00154 MEN , and these plants were further transformed with mouse prostaglandin H synthase ( PGH ) genes to produce prostaglandins . Mouse P23219 REA and P35354 REA cDNAs were amplified for expression as three isoforms : P23219 REA ( complete coding sequence with signal peptide ) , P23219 REA - Ma ( mature P23219 REA sequence , without signal peptide ) and P35354 REA ( complete coding sequence with signal peptide ) . P23219 REA transformants showed the highest activity , followed by P35354 REA transformants , whereas removal of the signal peptide resulted in almost complete loss of P23219 REA activity . In order to produce a physiologically active prostaglandin , the Trypanosoma brucei prostaglandin F synthase gene was combined with the mouse P23219 REA gene and the Mortierella alpina Δ ( 5 ) - desaturase on a binary vector . Transformation of DB00154 MEN - producing A . thaliana with this construct yielded transformants that successfully produced prostaglandin F .

Role of serotonin in the regulation of interferon-gamma production by human natural killer cells . Monocytes , recovered directly from peripheral blood by counter-current centrifugal elutriation ( CCE ) , were shown to provide two regulatory signals for induction of interferon-gamma ( P01579 REA ) in natural killer ( NK ) cells in response to interleukin - 2 ( P60568 REA ) : an upregulating signal and an inhibitory signal . The inhibitory signal was time-dependent , irreversible , and operating on a pretranslational level , as indicated by the inability of enriched NK cells to accumulate P01579 REA mRNA in the presence of elutriated monocytes . Monocyte-induced inhibition of P01579 REA production was abrogated by the biogenic amine serotonin , acting via the 5 - hydroxytryptamine , or serotonin ( P08908 REA ) , subset of serotonin receptors ( 5 - HTR ) . Thereby , serotonin effectively promoted P01579 REA production in the presence of monocytes . We conclude that serotonergic P08908 REA receptors transduce signals that are required for NK cells to produce P01579 REA in response to P60568 REA .

DB04946 SUB binding to human and rat dopamine and 5 - HT receptors . DB04946 SUB ( DB04946 SUB ; 1 - [ 4 - [ 3 - [ 4 - ( 6 - fluoro -1,2- benzisoxazol - 3 - yl ) - 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . DB04946 SUB displays affinity for dopamine D2 receptors and for 5 - Q13049 REA receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 REA and P28335 REA receptors and rat P50406 REA and P34969 REA receptors . DB04946 SUB displayed higher affinity for the dopamine D3 receptor ( Ki = 7.1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . DB04946 SUB displayed high affinity for the P50406 REA and P34969 REA receptors ( Ki = 42.7 and 21.6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 REA ( Ki = 5.6 nM ) than for the P28335 REA receptor ( Ki = 42.8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .

Passive smoke effects on cough and airways in young guinea pigs : role of brainstem DB05875 . Children raised with extended exposure to environmental tobacco smoke ( ETS ) experience increased cough and wheeze . This study was designed to determine whether extended ETS exposure enhances citric acid-induced cough and bronchoconstriction in young guinea pigs via a neurokinin - 1 ( NK - 1 ) receptor mechanism at the first central synapse of lung afferent neurons , the nucleus tractus solitarius . Guinea pigs were exposed to ETS from 1 to 6 weeks of age . At 5 weeks of age , guide cannulae were implanted bilaterally in the medial nucleus tractus solitarius at a site that produced apnea in response to the glutamate agonist D , L-homocysteic acid . At 6 weeks of age , either vehicle or a P25103 REA antagonist , DB05790 MEN , was injected into the nucleus tractus solitarius of the conscious guinea pigs who were then exposed to citric acid aerosol . ETS exposure significantly enhanced citric acid-induced cough by 56 % and maximal Penh ( a measure of airway obstruction ) by 43 % , effects that were attenuated by the P25103 REA antagonist in the nucleus tractus solitarius . We conclude that in young guinea pigs extended exposure to ETS increases citric acid-induced cough and bronchoconstriction in part by an P25103 REA mechanism in the nucleus tractus solitarius .

Synthesis of hybrid transition-metalloproteins via thiol-selective covalent anchoring of Rh-phosphine and Ru-phenanthroline complexes . The preparation of hybrid transition metalloproteins by thiol-selective incorporation of organometallic rhodium - and ruthenium complexes is described . Phosphine ligands and two rhodium-diphosphine complexes bearing a carboxylic acid group were coupled to the cysteine of PYP R52G , yielding a metalloenzyme active in the rhodium catalyzed hydrogenation of dimethyl itaconate . The successful coupling was shown by ( 31 ) P NMR spectroscopy and P19957 REA mass spectroscopy . In addition wild-type PYP ( PYP WT ) , PYP R52G and P15090 REA were successfully modified with a ( eta ( 6 ) - arene ) ruthenium ( II ) phenanthroline complex via a maleimide linker .

Behavioral and physiologic effects of genetic or pharmacologic inactivation of the DB05875 receptor ( NK1 ) . Depression and anxiety are among the most common diseases in the United States , thus constituting a substantial financial burden for the health care system . Experimental studies of these affective disorders to date have largely focused on the neurotransmitter pathways with well-established pathophysiologic roles , such as serotonergic , noradrenergic , and gamma-aminobutyric acid ( GABA ) - ergic systems ; agents modulating the activity of these pathways are known to be clinically effective . More recently , the neuropeptide DB05875 ( SP ) and its receptor ( the neurokinin - 1 receptor [ P25103 REA ] ) have been implicated in the pathophysiology of affective disorders , including depression . Earlier preclinical and clinical studies , though , did not provide a clear consensus on the role of SP in the regulation of affective behavior and related pathologic conditions . Recent studies in mice clearly demonstrate that both the genetic disruption and acute pharmacologic blockade of the P25103 REA result in marked reduction in anxiety-like behavior and stress-related responses . In parallel with these behavioral effects , physiologic changes , such as an increased firing rate of 5 - hydroxytryptamine ( 5 - HT ) neurons in the dorsal raphe nuclei and a desensitization of presynaptic P08908 REA inhibitory autoreceptors , were observed . These findings provide further evidence for the regulatory role of the SP - P25103 REA system in modulation of affective behavior and indicate that its effects are mediated , at least in part , via the serotonergic system . Future studies will attempt to delineate the interaction between the SP - P25103 REA system and various neurotransmitter pathways in greater detail and to address the specific role ( s ) of this system in different brain regions .

Inhibition of Q16552 REA as a pharmacological approach for Q9UKU7 . Several experimental approaches have been utilized , in order to critically examine the roles of Q16552 REA family members in intestinal inflammation . These approaches have included : ( 1 ) the use of Q16552 REA and Q96PD4 - deficient mice , ( 2 ) specific antibodies directed against Q16552 REA , ( 3 ) an Q16552 REA vaccine , ( 4 ) methods to block the Q16552 REA receptor and ( 5 ) small-molecule inhibitors of Q16552 REA . Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease ( Q9UKU7 ) , using specific strains of Q16552 REA - deficient mice . This paper will review the preclinical results using various pharmacological approaches [ specific Q16552 REA antibodies , an Q16552 REA receptor fusion protein , IL - 12 / IL - 23 p40 subunit and Q16552 REA vaccine approaches , as well as a small molecule inhibitor ( Vidofludimus ) ] to inhibit Q16552 REA in animal models of Q9UKU7 . Recent clinical results in patients with Q9UKU7 will also be discussed for DB09029 MEN ( an Q16552 REA antibody ) , Brodalumab ( an Q16552 REA receptor antibody ) and two small-molecule drugs ( Vidofludimus and DB08895 ) , which inhibit Q16552 REA as part of their overall pharmacological profiles . This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti - Q16552 REA drugs , as related to drug pharmacodynamics , Q16552 REA receptor subtypes and other pertinent factors . Finally , future pharmacological approaches of interest will be discussed , such as : ( 1 ) Retinoic acid receptor-related orphan nuclear receptor gamma t ( Rorγt ) antagonists , ( 2 ) P10276 REA ( RARα ) antagonists , ( 3 ) Pim - 1 kinase inhibitors and ( 4 ) Dual small-molecule inhibitors of NF-κB and P40763 REA , like synthetic triterpenoids .

Functional characterization of the novel antipsychotic iloperidone at human D2 , D3 , alpha 2C , P50406 REA , and P08908 REA receptors . DB04946 SUB has demonstrated an interesting monoamine receptor profile in radioligand binding studies , with nanomolar affinity for certain noradrenaline , dopamine , and serotonin receptors . In this study , the agonist / antagonist activity of iloperidone was determined in cell lines expressing recombinant human D ( 2A ) , D ( 3 ) , alpha ( 2C ) , 5 - HT ( 1A ) , or 5 - HT ( 6 ) receptors . With the exception of 5 - HT ( 6 ) receptors , these receptors are negatively coupled to cyclase . Thus , after stimulation with forskolin , the agonists dopamine ( at D ( 2A ) and D ( 3 ) ) , noradrenaline ( at alpha ( 2C ) ) , or 8 - OH-DPAT ( at 5 - HT ( 1A ) ) induced a reduction in DB02527 accumulation . Conversely , activation of the 5 - HT ( 6 ) receptor by 5 - HT led to an increase in DB02527 accumulation . DB04946 SUB alone was devoid of significant agonist activity but inhibited the agonist response in all 5 cell lines in a surmountable and concentration-dependent fashion . DB04946 SUB was most potent at D ( 3 ) receptors ( pK ( B ) 8.59 + / - 0.20 ; n = 6 ) , followed by alpha ( 2C ) ( pK ( B ) 7.83 + / - 0.06 ; n = 15 ) , 5 - HT ( 1A ) ( pK ( B ) 7.69 + / - 0.18 ; n = 10 ) , D ( 2A ) ( pK ( B ) 7.53 + / - 0.04 ; n = 11 ) and 5 - HT ( 6 ) ( pK ( B ) 7.11 + / - 0.08 ; n = 11 ) receptors .

Synthesis and biological activity of DB00644 antagonists modified at position 3 with 3 - ( 2 - methoxy - 5 - pyridyl ) - alanine . DB06699 MEN is a potent very long-acting DB00644 antagonist after subcutaneous administration . In this paper , we describe the synthesis of two analogs of degarelix incorporating racemic 3 - ( 2 - methoxy - 5 - pyridyl ) - alanine ( 2 - OMe - 5Pal , 5 ) at position 3 . The two diastereomers were separated by reverse-phase high-performance liquid chromatography ( RP-HPLC ) and the absolute stereochemistry at position 3 in the peptides was determined by enzymatic digestion with proteinase K . These analogs were tested in vitro for their ability to antagonize the P30968 REA and in vivo for duration of action in a castrated male rat assay . Analog 7 with D2 - OMe - 5Pal was potent in vitro ( IC50 = 5.22 nM ) ; however , analog 8 with Q401N2 - OMe - 5Pal at position 3 in degarelix lost potency as an antagonist of the human P30968 REA ( IC50 = 36.95 nM ) . Both the analogs were found to be short-acting in vivo .

Serotonin induces the expression of tissue factor and plasminogen activator inhibitor - 1 in cultured rat aortic endothelial cells . Serotonin ( 5 - hydroxytryptamine , or 5 - HT ) , released from activated platelets , not only accelerates aggregation of platelets but also is known to promote mitosis , migration , and contraction of vascular smooth muscle cells ( VSMCs ) . These effects are considered to contribute to thrombus formation and atherosclerosis . The aim of this study was to investigate the effects of 5 - HT on the expressions of coagulative and fibrinolytic factors in rat aortic endothelial cells . Endothelial cells were stimulated with various concentrations of 5 - HT ( 0.1 approximately 10 microM ) , and the expressions of tissue factor ( TF ) , tissue factor pathway inhibitor ( P10646 REA ) , plasminogen activator inhibitor - 1 ( P05121 REA ) , and tissue-type plasminogen activator ( TPA ) messenger RNAs ( mRNAs ) were evaluated by Northern blot analysis . The activities of TF and P05121 REA were also measured . TF and P05121 REA mRNA were increased significantly in a concentration - and time-dependent manner . However , P10646 REA and TPA mRNA expression did not change . The inductions of TF and P05121 REA mRNAs were inhibited by a 5 - HT1 / 5 - HT2 receptor antagonist ( methiothepin ) and a selective 5 - Q13049 REA receptor antagonist ( D6RGH6 - 9042 ) . These results indicate that 5 - HT increases procoagulant activity and reduces fibrinolytic activities of endothelial cells through the 5 - Q13049 REA receptor . It was concluded that the modulation of procoagulant and hypofibrinolytic activities of endothelial cells by 5 - HT synergistically promotes thrombus formation at the site of vessel injury with the platelet aggregation , VSMC contraction , and VSMC proliferation .

Fc receptor blockade and immune thrombocytopenic purpura . Inhibition of antibody-coated platelet destruction in patients with immune thrombocytopenic purpura ( ITP ) is a well-known mechanism of treatment effect . A number of interventions that would ameliorate the thrombocytopenic effect of ITP patient plasma when infused into normal recipients were demonstrated in 1965 . Subsequently , the antibody-coated chromium-labeled red blood cell clearance study was developed to allow direct in vivo assessment of Fc receptor ( FcR ) blockade . This was first demonstrated for corticosteroids but more extensive investigation began with the study of intravenous infusions of gammaglobulin ( DB00028 MEN ) . The unequivocal demonstration of FcR blockade following DB00028 MEN Initiated novel approaches . One involved the infusion of a monoclonal anti-FcRIII ligand-blocking antibody into patients with refractory ITP . The efficacy of this treatment demonstrated that FcR blockade was not an epiphenomenon but rather an important mechanism of the increase in the platelet count in patients with ITP . Confirmation of its importance was obtained from the infusion of intravenous ( IV ) anti-D and the use of the isolated Fc piece of IgG . Recent studies have begun to explore the possibility of a monoclonal anti - P12314 REA and monoclonal anti-Ds . In summary , FcR blockade is an important mechanism of treatment effect in patients with ITP . Cytokine release as a consequence of this interaction and other immunomodulatory effects have only begun to be studied .

Signaling and antiproliferative effects mediated by DB00644 receptors after expression in breast cancer cells using recombinant adenovirus . DB00644 receptors ( DB00644 - Rs ) are found in human cancers , including those of the breast , and DB00644 can inhibit the growth of cell lines derived from such cancers . Although pituitary and extrapituitary P30968 REA transcripts appear identical , their functional characteristics may differ . Most extrapituitary DB00644 - Rs have low affinity for DB00644 analogs and may not activate P98160 REA or discriminate between agonists and antagonists in the same way as pituitary DB00644 - Rs . Here we have assessed whether DB00644 - Rs expressed exogenously in breast cancer cells differ from those in gonadotropes . We found no evidence for endogenous DB00644 - Rs in MCF 7 cells , but after infection with adenovirus expressing the P30968 REA ( Ad P30968 REA ) at a multiplicity of infection of 10 or greater , at least 80 % expressed DB00644 - Rs . These had high affinity ( K ( d ) for [ ( 125 ) I ] buserelin , 1.4 nM ) and specificity ( rank order of potency , buserelin > DB00644 > > chicken DB00644 - II ) and mediated stimulation of [ ( 3 ) H ] IP accumulation . Increasing viral titer [ from multiplicity of infection , 3-300 ] increased receptor number ( 10,000- 225,000 sites / cell ) and [ ( 3 ) H ] IP responses . DB00644 stimulated P28482 REA phosphorylation in Ad P30968 REA - infected cells , and this effect , like stimulation of [ ( 3 ) H ] IP accumulation , was blocked by P30968 REA antagonists . DB00644 also inhibited [ ( 3 ) H ] thymidine incorporation into Ad P30968 REA - infected cells ( but not control cells ) . This effect was mimicked by agonist analogs and inhibited by two antagonists . Thus , when exogenous DB00644 - Rs are expressed at density comparable to that in gonadotropes , they are functionally indistinguishable from the endogenous DB00644 - Rs in gonadotropes , and increasing expression of high affinity DB00644 - Rs can dramatically enhance the direct antiproliferative effect of DB00644 agonists on breast cancer cells .

Synthesis and biological evaluation of novel pyrrolidine -2,5- dione derivatives as potential antidepressant agents . Part 1 . A series of 3 - ( 1H - indol - 3 - yl ) pyrrolidine -2,5- dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by ( 1 ) H NMR , ( 13 ) C NMR and P19957 REA - HRMS spectra data . All tested compounds proved to be potent P08908 REA receptor and serotonin transporter protein ( P31645 REA ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 REA and P31645 REA . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 REA receptor and P31645 REA confirm the results of biological tests . Due to high affinity for the P08908 REA receptor and moderate affinity for P31645 REA , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 REA , P34969 REA and 5 - Q13049 REA receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 REA receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 REA receptor agonists .