Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Presynaptic autoreceptor-mediated modulation of dopamine (DA) synthesis was evaluated as the inhibition of tyrosine hydroxylase activity by enantiomeric mono- and dihydroxyaporphines with minced striatal tissue from rat brain. The isomers of N-n-propylnorapomorphine (NPA) both inhibited tyrosine hydroxylase activity [IC50 = 0.3 and 1.0 microM for (R)-(-)- and (S)-(+)-NPA, respectively; R/S potency = 3.6]. Their effects were fully blocked by the nonselective DA receptor antagonist fluphenazine, as well as by the D2-selective antagonist spiperone, but not by the D1 antagonist SCH-23390. These results suggest a D2-type autoreceptor-mediated inhibition of DA synthesis, with limited enantiomeric selectivity of this catechol-aporphine. The corresponding monohydroxy analogs, (R)-(-)- and (S)-(+)-11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) were about 100 times less potent (IC50 = 42 and 87 microM, respectively) than the NPA isomers in fully inhibiting the enzyme activity in normal tissue but, after depletion of endogenous DA by acute in vivo pretreatment with reserpine (which did not alter the number of D1 or D2 specific binding sites), (R)-(-)-11-OH-NPa was a highly potent but partial agonist (IC25 = 7 nM). Fluphenazine and spiperone fully antagonized the inhibition of tyrosine hydroxylase by (R)-(-)-11-OH-NPa in reserpinized tissue, but SCH-23390 was ineffective. Actions mediated by endogenous DA probably contribute to the effect of high concentrations of (R)-(-)-11-Oh-NPa to evoke a full inhibition of DA synthesis, but its high potency partial agonist effects appear to be mediated by D2-autoreceptors. (S)-(+)-11-OH-NPa was a very weak partial agonist in reserpinized tissue, with an IC25 = 30 microM (essentially the same as normal tissue); thus, (R)-(-)-11-OH-NPa was greater than 4,000 times more potent than its S-(+)-enantiomer in the absence of endogenous DA. These results demonstrate that NPA, which contains a catechol moiety, acts as a full agonist to inhibit striatal DA synthesis via a presynaptic autoreceptor of the D2 type, with only slight stereoselectivity, and that its monohydroxy analog is a very potent but partial D2 autoreceptor agonist, with very high stereoselectivity.
Mol Pharmacol 1990 Jul
PMID:Presynaptic inhibition of dopamine synthesis in rat striatal tissue by enantiomeric mono- and dihydroxyaporphines. 197 25

We describe an improved synthesis and properties of fluphenazine-mustard, a potent phenothiazine having an alkylating chlorethylamine chain in its structure. The drug possesses anticalmodulin activity equivalent to the parent compound, but unlike fluphenazine dihydrochloride, the mustard derivative irreversibly antagonizes the ability of calmodulin to activate cyclic nucleotide phosphodiesterase. This property is partially calcium-dependent and can be overcome by coincubation with excess fluphenazine dihydrochloride. The compound irreversibly inactivated calmodulin when incubated with intact cells and caused single-stranded breakage of DNA. Fluphenazine-mustard possesses potent antiproliferative and cytotoxic properties against malignant cell lines that are likely to be mediated through both of these actions.
Mol Pharmacol 1987 Sep
PMID:Pharmacological properties of fluphenazine-mustard, an irreversible calmodulin antagonist. 367 Feb 76

The dopamine-stimulated adenylate cyclase activity was studied both in vivo and in vitro in the central nervous system of the bivalve mollusc Mytilus edulis. Dopamine, epinine, and apomorphine stimulated the enzyme system. Fluphenazine, haloperidol, chlorpromaxine, and to a lesser extent BOL inhibited the dopamine-stimulated adenylate cyclase. Etorphine, beta-endorphine, DALA, and methionine enkephalin depressed cyclic AMP levels. This phenomena was naloxone reversible. In addition, the opioids inhibited the stimulation of adenylate cyclase by dopamine. This phenomena was also naloxone reversible. The study demonstrates an interaction among dopamine, the opioids, and cyclic AMP.
Cell Mol Neurobiol 1981 Mar
PMID:Characterization of the dopamine stimulated adenylate cyclase in the pedal ganglia of Mytilus edulis: interactions with etorphine, beta-endorphin, DALA, and methionine enkephalin. 628 25

Classical antipsychotics, such as fluphenazine, influence neurotransmission by blocking both dopamine D1- and D2-receptors which in turn results in widespread adaptive changes in the neurochemistry of the basal ganglia. The purpose of the present study was to determine the role of D1-receptors in mediating some of these neurochemical events, including changes in D1- and D2-receptor binding, and the expression of preproenkephalin and glutamic acid decarboxylase mRNAs. For these experiments, rats were given a depot injection of fluphenazine decanoate or injected twice daily for 21 days with the D1-receptor antagonist SCH-23390. An additional group received both fluphenazine and SCH-23390 and controls were given saline. Fluphenazine administration decreased D2-receptor binding throughout the basal ganglia while SCH-23390 was without effect. In contrast to the uniform reduction in D2-receptor binding, fluphenazine altered D1-receptor binding in a region-dependent manner. Region-dependent changes were also observed in animals given SCH-23390 which increased binding in the entopeduncular nucleus and posterior caudate-putamen without affecting other brain regions. Both fluphenazine and SCH-23390 significantly enhanced preproenkephalin and glutamic acid decarboxylase (GAD) mRNA expression in the anterior striatum. Fluphenazine also increased GAD mRNA levels in the entopeduncular nucleus. Together, these results indicate that the attenuation of D1-receptor-mediated neurotransmission modulates a number of clinically relevant neurochemical processes in the basal ganglia.
Brain Res Mol Brain Res 1997 Oct 03
PMID:Modulation of basal ganglia neurotransmission by the classical antipsychotic fluphenazine is due in part to the blockade of dopamine D1-receptors. 938 79

The degradation of chromogenic substrates and oligopeptides by the 20S proteasome is markedly enhanced and the generation of antigens for presentation by the MHC class-I system is facilitated by combination with an activator protein known as PA28 or 11S reg. We have described the properties of a PA28-proteasome modulator, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinol which shifts the pathway of peptide hydrolysis by the activated proteasome to products terminating in an acidic amino acid at the expense of products terminating in a hydrophobic amino acid. We now report that piperazinyl phenothiazines and several other antipsychotic drugs modulate the PA28-20S activated proteasome in an opposite manner. Fluphenazine, trifluoperazine and prochlorperazine antagonize the peptidylglutamyl peptide bond hydrolyzing activity of the activated proteasome much more strongly than the chymotrypsinlike activity. The chicken ovalbumin immunodominant epitope SIINFEKL is degraded by the activated proteasome to SIINFE and SIINF in approximately equimolar amounts. Piperazinyl phenothiazines promote formation of SIINF whereas Psi-ol promotes formation of SIINFE. PA28- proteasome modulators by modifying the profile of peptides produced by the activated proteasome, may either enhance or suppress the immune response.
Mol Biol Rep 1999 Apr
PMID:Modulators of the activation of the proteasome by PA28 (11S reg). 1036 45

The effects of two different classes of calmodulin antagonists on the catalytic activities of purified pyruvate dehydrogenase (PDH) phosphatase and PDH complex (PDC) were studied. In general, PDH phosphatase was more strongly inhibited than PDC by the calmodulin antagonists with the following potency order: fluphenazine > chlorpromazine > thioridazine > triflupromazine. Promazine and two sulfonamides (W-5 and W-7) did not suppress PDH phosphatase activity at 1 mM concentrations, while about 20% of PDC activity was inhibited by these antagonists. Fluphenazine-mediated inhibition of PDH phosphatase was observed with the purified PDC as well as intact mitochondria. Although Ca2+ stimulates PDH phosphatase activity, the addition of exogenous Ca2+ did not overcome the inhibition by calmodulin antagonists. These results suggest that the suppression of PDH phosphatase activity is dependent upon the structure of the individual calmodulin antagonist and appears to be Ca(2+)-independent. Kinetic analysis showed a noncompetitive inhibition of PDH phosphatase by fluphenazine, indicating that it binds to different site(s) from the catalytic site of the enzyme.
Biochem Mol Biol Int 1999 Jun
PMID:Noncompetitive, Ca(2+)-independent inhibition of pyruvate dehydrogenase phosphatase by fluphenazine. 1041 Feb 49

Fluphenazine (FPh) exhibited antimutagenic activity in lymphocyte cultures, markedly decreasing genotoxic effects of standard mutagenic agents present in cell cultures. However, the strong pharmacological activity of this neuroleptic drug, together with its serious side effects on the central nervous system, limits its use as an antimutagenic compound. In this paper we describe a route of chemical synthesis of FPh analogues that are more hydrophilic than the model compound, thus probably penetrate more weakly through the blood-brain barrier. These new analogues were tested for their antimutagenic and pro-apoptotic activities in human lymphocyte cultures, genotoxically damaged in vitro with benzo[a]pyrene [40 microM, 30 min] and subsequently cultured for 48 h in the presence of the tested compounds. The fluphenazine analogues enhanced apoptosis in genotoxically damaged lymphocytes more strongly than the model compound did. The increase of apoptotic cell frequency was the highest with compound 4a [2-(trifluoromethyl)-10-[3-(diethanolamino)-2-hydroxypropyl] phenothiazine]--a 35% higher effect than that of fluphenazine. The cytotoxicity of derivative 4a was the lowest among the tested compounds; it was 60% lower than that of fluphenazine. The antimutagenic effect of 4a was about 10% stronger than that of fluphenazine. Compound 4a also had the highest hydrophilicity of the new FPh analogues. Compound 4a was chosen for further study as a potentially usable antimutagen that would only weakly penetrate the central nervous system.
Cell Mol Biol Lett 2003
PMID:Antimutagenic activity of new analogues of fluphenazine. 1466 16

The serotonin type 3 (5-HT(3)) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT(3) receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT(2)) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT(3) receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na(+)-inward currents through 5-HT(3) receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT(3) receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca(2+) influx, measured as a change in intracellular Ca(2+) concentrations ([Ca(2+)](i)). All neuroleptic drugs, but not risperidone, antagonized Na(+)- and Ca(2+)-inward currents evoked by 5-HT (10 microM for 2 s and 1 microM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC(50) values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT(3) receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na(+) and Ca(2+) currents. Since 5-HT(3) receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT(3) receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.
Mol Psychiatry 2004 Sep
PMID:Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner. 1502 94