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PubMed1996

Photolabile amiloride derivatives as cation site probes of the Na,K-ATPase.

Treatment of purified canine renal Na,K-ATPase with a range of photoactivatable amiloride derivatives results in inhibition of ATPase activity prior to illumination. Inhibition by amiloride derivatives substituted on a guanidium N could not be prevented by the presence of either K or Na; however, these cations could protect the enzyme against inhibition by derivatives substituted on the 5-position of the pyrazine ring. In the case of 5-(N-ethyl-[2'-methoxy-4'-nitrobenzyl])amiloride (NENMBA), the presence of monovalent cations (Na, K, and Rb) protected the enzyme effectively against inhibition, with concentrations in the millimolar range. ATP did not prevent inhibition; furthermore, native and NENMBA-treated enzyme exhibited normal levels of high affinity [3H]ADP (and hence ATP) binding. The rate of inhibition increased with increasing concentrations of NENMBA. Extensive washing of NENMBA-inhibited enzyme did not restore ATPase activity, showing that NENMBA has an extremely slow off-rate for dissociation from its inhibitory site. Partially inhibited enzyme could be rapidly pelleted and resuspended in NENMBA-free buffer and inhibition was observed to continue, albeit at a somewhat diminished rate, suggesting that NENMBA gains access to its inhibitory site after partitioning into the lipid phase rather than directly from the aqueous solution. Photolysis of NENMBA-inhibited enzyme resulted in covalent incorporation of the reagent into the alpha-subunit of the Na,K-ATPase, as observed by separation of labeled protein on a Laemmli gel and Western analysis using a polyclonal amiloride antibody. Almost all of the covalent labeling could be prevented by the presence of Rb in the incubation and labeling medium. These results suggest that NENMBA inhibits the Na, K-ATPase by disruption of the cation transport domain rather than the catalytic domain of the enzyme and that it promises to be a useful tool for cation site localization.

Affinity Labels↗

PubMed1998

Generation of superoxide anion by succinate-cytochrome c reductase from bovine heart mitochondria.

Production of superoxide anion (O-2), measured as the chemiluminescence of the 2-methyl-6-(p-methoxyphenyl)-3, 7-dihydroimidazo[1,2-a]pyrazin-3-one hydrochloride (MCLA)-O-2 adduct, was observed during electron transfer from succinate to cytochrome c by reconstituted succinate-cytochrome c reductase-phospholipid vesicles replenished with succinate dehydrogenase. Addition of carbonyl cyanide p-trifluoromethoxyphenylhydrazone or detergent to the reconstituted reductase-phospholipid vesicles abolished O-2 production, suggesting that O-2 generation is caused by the membrane potential generated during electron transfer through the cytochrome bc1 complex. Production of O-2 was also observed during electron transfer from succinate to cytochrome c by antimycin-treated reductase, in which approximately 99.7% of the reductase activity was inhibited. The rate of O-2 production was closely related to the rate of antimycin-insensitive cytochrome c reduction. Factors affecting antimycin-insensitive reduction of cytochrome c also affected O-2 production and vice versa. When the oxygen concentration in the system was decreased, the rate of O-2 production and cytochrome c reduction by antimycin-treated reductase decreased. When the concentrations of MCLA and cytochrome c were increased, the rate of O-2 production and cytochrome c reduction by antimycin-treated reductase increased. The rate of antimycin-insensitive cytochrome c reduction was sensitive to Qo site inhibitors such as 5-undecyl-6-hydroxy-4,7-dioxobenzothiazole. These results indicate that generation of O-2 during the oxidation of ubiquinol by the cytochrome bc1 complex results from a leakage of the second electron of ubiquinol from its Q cycle electron transfer pathway to interact with oxygen. The electron-leaking site is located at the reduced cytochrome b566 or ubisemiquinone of the Qo site because addition of MCLA to antimycin-treated cytochrome bc1 complex, in the presence of catalytic amounts of succinate-cytochrome c reductase, delayed cytochrome b reduction by succinate. In the presence of oxidized cytochrome c, purified succinate dehydrogenase also catalyzed oxidation of succinate to generate O-2. When succinate dehydrogenase was reconstituted with the bc1 particles to form succinate-cytochrome c reductase, the production of O-2 diminished. These results suggest that reduced FAD of succinate dehydrogenase is the electron donor for oxygen to produce O-2 in the absence of their immediate electron acceptor and in the presence of cytochrome c.

Animals↗

PubMed2002

N-O glucuronidation: a major human metabolic pathway in the elimination of two novel anti-convulsant drug candidates.

1. The urinary metabolites of the anti-convulsant compound 4-amino-1-(2,6-difluorobenzyl)-1H-1,2,3-triazolo[4,5-c]-pyridine hydrochloride (GI265080) obtained following a single oral dose to man have been detected and quantified relative to each other using 19F-NMR spectroscopy. 2. The human urinary metabolites of GI265080 were isolated using semipreparative HPLC and unequivocally characterized using 1H-NMR spectroscopy, two-dimensional heteronuclear NMR spectroscopy and mass spectrometry. The assignments of the N-(5)-oxide and the N-(5)-O-glucuronide metabolites of GI265080 were further confirmed by independent synthesis. The urinary metabolites obtained following single oral doses to dog and rat have also been isolated and characterized. 3. The human urinary metabolites of GI265080 comprise the N-(5)-oxide, the quaternary N+-(5)-glucuronide, the 7-hydroxy glucuronide and a glucuronide conjugate of the N-(5)-oxide. The N-(5)-O-glucuronide conjugate is a novel species in human metabolism and is a significant route of elimination of GI265080 in man. 4. The urinary metabolites of the potential anti-convulsant GW273293 (6-amino-3-(2,3,5-trichlorophenyl)pyrazin-2-ylamine) obtained following a single oral dose to man have also been isolated and characterized. The formation of a novel N-O-glucuronide was also observed and was shown to constitute a significant route of elimination of GW273293 in man.

Animals↗

PubMed1998

Partial hepatoprotective effects of allylthiobenzimidazole in the absence of cytochrome P4502E1 suppression: effects on epoxide hydrolase, rGSTA2, rGSTA3/5, rGSTM1 and rGSTM2 expression.

1. 2-(Allylthio)pyrazine protects the liver against acetaminophen- and carbon tetrachloride-induced injury through inhibition of cytochrome P4502E1 and induction of glutathione S-transferases (GSTs). By comparison, the effects of allylthiobenzimidazole (ATB) on the levels of several hepatic cytochrome P450, microsomal epoxide hydrolase (mEH) and GST expression have been studied in the rat herein. 2. Western immunoblotting analyses revealed that ATB treatment (50 mg/kg/day for 5 days) failed to alter cytochrome P4501A2, P4502B1/2 and P4502E1 levels in the liver, whereas the expression of P4502C11 was reduced approximately 50% by ATB. 3. Treatment of rat with a single dose of ATB resulted in 2-21-fold increases in mEH mRNA levels at 24 h with an ED50 = 60 mg/kg. mEH mRNA level was elevated 9- and 21-fold at 12 and 24 h after treatment at 200 mg/kg respectively as compared with control. Western blot analysis revealed that ATB induced mEH protein levels by 2-fold relative to control. 4. ATB induced the major GST mRNA levels as a function of dose, resulting in rGSTA2, rGSTA3/5 and rGSTM1 mRNA levels elevated by 20-, 6- and 8-fold at 24 h respectively. The relative rGSTM2 mRNA level was minimally affected. Time-course studies showed that mEH, rGSTA2 and rGSTM1 mRNA levels were significantly increased at 12 and 24 h after ATB treatment, returning to control levels by 48 h. Treatment of rat with ATB (20-50 mg/kg/day for 5 days) resulted in 2-3-fold increases in mEH, rGSTA1/2, rGSTA3/5 and rGSTM1 mRNA levels with the induction of GST subunits. 5. ATB failed to block carbon tetrachloride-induced liver toxicity in rat and mouse. ATB treatment (50 mg/kg day for 3 days) prior to a lethal dose of acetaminophen significantly reduced acetaminophen-induced liver toxicity in mouse, as assessed by both plasma alanine aminotransferase activity and histopathological examination. The 30-day survival rate of mouse gamma-irradiated at 8 Gy failed to be improved by ATB pretreatment (100 mg/kg/day for 2 days). 6. These results provided evidence that ATB stimulated mEH and GST gene expression at early times and reduced the P4502C11 level in the absence of P4502E1 suppression. ATB was only partially effective in protecting the liver against toxicant-induced injury despite the presence of allylthio moiety in its chemical structure.

Animals↗

PubMed1999

S-methylation of 2-mercaptopyrazine in rat liver microsomes and cytosol.

1. 2-(Allylthio)pyrazine (2-AP) has been demonstrated to protect the liver against toxicants by inhibiting CYP2E1 activity. Since 2-mercaptopyrazine (2-MP) is presumed to be a metabolite of 2-AP, the experiments were performed to determine whether rat liver microsomal and/or cytosolic preparations could catalyse the S-methylation of 2-MP. 2. It was found that both rat liver microsomes and cytosol could catalyse the S-methylation of 2-MP. The microsomal activity displayed biphasic substrate kinetics, with apparent Km = 8.44+/-2.68 and 417+/-74 microM for the high- and low-affinity activities respectively. The high-affinity activity had an apparent Km for S-adenosyl-L-methionine (Ado-Met) of 3.52 microM. The cytosolic activity also displayed biphasic substrate kinetics, with apparent Km of 3.26+/-0.62 and 91.6+/-23.1 microM for the high- and low-affinity activities respectively. 3. The microsomal S-methylation of 2-MP was inhibited by 2,3-dichloro-alpha-methylbenzylamine (DCMB), SKF-525A and benzylamine, known microsomal thiol methyltransferase (TMT) inhibitors, whereas cytosolic activity was inhibited by anisic acid and 3-chlorobenzoate, which also inhibit cytosolic thiopurine methyltransferase (TPMT). Both activities were inhibited by S-adenosyl-L-homocysteine (Met-Hcy). 4. These results suggest that both TMT and TPMT may be involved in the in vivo methylation of 2-MP.

Aniline Compounds↗

PubMed2005

Coelenterazine (marine bioluminescent substrate): a source of inspiration for the discovery of novel antioxidants.

Coelenterazine and derivatives were initially considered in the scientific community for their (bio)luminescent properties. Now, another interest of such hetero-bicycles has been pointed out by the discovery of remarkable antioxidative properties, and an unique mode of action as a "cascade": the mother-compound (imidazolopyrazinone) is transformed by ROS into a daughter-compound (2-amino-pyrazine) also endowed with antioxidative properties. This review illustrates the therapeutic potential of synthetic imidazolopyrazinones (coelenterazine analogues): chemical reactivity assays with singulet oxygen, radical anion superoxide, peroxynitrite, and radicals formed during lipid and LDL peroxidation, cellular tests of protection against oxidative stress using keratinocyte, hepatocyte, neuronal and erythrocyte cells, and finally in vivo evaluation in a hamster model of ischemia-reperfusion, are fully described.

Animals↗

PubMed1998

Synthesis and antiviral evaluation of pyrazinones substituted with acyclic chains.

The synthesis of a series of pyrazine analogues of the anti-herpes compound, acyclovir is described. These syntheses were accomplished by various methods: in the presence of a Lewis acid or NaH for hydroxyethoxymethyl and hydroxybutyl groups or by sequential oxidation/reduction of 1-(beta-D-ribofuranosyl)-2-pyrazinones for 2',3'-acyclonucleosides. Antiviral (HSV-1, CMV, Cox B4, HIV-1) properties of these compounds were determined.

Antiviral Agents↗

PubMed1998

Potential antiviral agents. Part II. Synthesis and antiviral evaluation of pyrazinones substituted with acyclic chains.

The synthesis of a series of 4'-substituted hydroxybutyl pyrazine analogues of the anti-herpes compound, acyclovir, is described. The compounds were characterized with 1H and 13C nmr, mass and IR spectroscopy. Antiviral (HSV-1, CMV, Cox B4, HIV-1) properties of these compounds were examined. None of these compounds were active against these viruses.

Acyclovir↗

PubMed1986

Capsicum--production, technology, chemistry, and quality. Part III. Chemistry of the color, aroma, and pungency stimuli.

The spice capsicum, the fruits of the genus Capsicum (Family Solanaceae), is a very popular food additive in many parts of the world, valued for the important sensory attributes of color, pungency, and aroma. A large number of varieties are widely cultivated and traded. The characteristic carotenoids of the bright red paprika and cayenne-type chillies, the high character impact aroma stimuli, the methoxy pyrazine of green bell capsicum, the esters of ripe tabasco and the highly potent pungency stimuli, and the capsaicinoids of African and other Asian varieties of chillies, have been of great interest to chemists and biochemists. Research workers in other disciplines such as genetics and breeding, agriculture, and technology have been interested in this spice to develop new varieties with combinations of different optimal levels of the stimuli for the sensory attributes and to maximize production of storable products for specific end uses. Physiologists have been intensely studying the action of the highly potent pungency stimuli and social psychologists the curious aspect of growing acceptance and preference for the initially unacceptable pungency sensation. In the sequential review of all these aspects of the fruit spice Capsicum, the earlier two parts covered history, botany, cultivation and primary processing, and processed products, standards, world production, and trade. In Part III, the chemistry, the compositional variations, synthesis and biosynthesis of the functional components, the carotenoids, the volatiles, and the capsaicinoids are comprehensively reviewed.

Capsaicin↗

PubMed2001

Protection against nitrofurantoin-induced oxidative stress by coelenterazine analogues and their oxidation products in rat hepatocytes.

Coelenterazine (3,7-dihydro-2-(p-hydroxybenzyl)-6-(p-hydroxyphenyl)-8-benzylimidazolo[1,2-a]pyrazin-3- one) is a substrate for the bioluminescence reaction in many marine animals. Recent work showed that CLZn, its synthetic analogue CLZm, and their common oxidation product coelenteramine (CLM) have strong antioxidative properties in acellular lipid peroxidation systems as well as in rat hepatocytes subjected to tert-butyl hydroperoxide (t-BHP). Here, we analyzed the ability of CLZm and several imidazolopyrazinone (IMPZs) analogues to protect primary cultures of rat hepatocytes against a nitrofurantoin (NF)-induced oxidative stress. Comparison of protection capabilities with reference antioxidants yielded the following ranking: CLZm >>> BHT >Trolox C((R)) > probucol > alpha-tocopherol. The comparison of CLZm with analogues lacking the phenol group in R(1) revealed no differences although the presence of this phenol conferred superior protection against t-BHP. CLM, as well as its methoxylated analogue mCLM which lacks chain-breaking properties, were equally potent in preventing cellular damage caused by NF. mCLM and alpha-naphthoflavone, an inhibitor of cytochrome P450 (CYP450) IAI, similarly protected cells against NF-induced mortality and also equally inhibited EROD activity in methylcholanthrene-induced hepatocytes. The inhibition of EROD by CLZm and CLM was less pronounced. We suggest that the extent of protection conferred by IMPZs against NF-toxicity reflects both the occurrence of antioxidative properties detoxifying ROS produced within cells and inhibitory actions on CYP450 isoforms involved in the bioreduction of NF.

Animals↗

PubMed2002

A phase II study of CI-980 in previously untreated extensive small cell lung cancer: an Ohio State University phase II research consortium study.

CI-980, (ethyl (S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b] pyrazine-7-yl) carbamate 2-hydroxyethansulfonate (1:1)), is a water-soluble mitotic inhibitor. It acts by binding to the colchicine-binding site on tubulin, a site different from that of the vinca alkaloids, inhibiting tubulin polymerization. Cells exposed to CI-980 accumulate in M phase and die. In preclinical tumor models, CI-980 showed a broad spectrum of activity, including in multi-drug resistant tumor cell lines, with activity at least equal to that of vincristine. Extensive small cell lung cancer, despite its responsiveness to chemotherapy, is usually an incurable disease with survival in patients of less than one year. Due to the preclinical activity of CI-980 and its similar mechanism of action to drugs effective in small cell lung cancer, a phase II trial in extensive small cell lung cancer was initiated by The Ohio State University Phase II Research Consortium. A "window of opportunity" design was chosen where a short six-week trial of the drug was given unless there was significant objective response. Twelve patients were entered in the study and underwent a total of 16 cycles of chemotherapy. The median age of the patients was 54 years old (range 34-71) and performance status was ECOG 0 (four patients), ECOG 1 (seven patients), and ECOG 2 (one patient). The patients were treated with a 72-hr infusion at a dose of 4.5 mg/m2/day. Toxicity was predominantly myelosuppression with granulocytopenia (nine episodes), and anemia (seven episodes). There were no objective responses with 11 patients being removed from study due to progressive disease. Evaluation of leukocyte microtubule structure in peripheral blood revealed microtubule depolymerization, which was seen after treatment (t = 72 hr) and was reversible within 24 hr of stopping the drug. We conclude that despite antitumor activity demonstrated in preclinical studies, CI-980 does not have biological activity in previously untreated small cell lung cancer at this dose and infusion protocol.

Adult↗

PubMed1976

Effect of amiloride and some of its analogues of cation transport in isolated frog skin and thin lipid membranes.

The inhibition of short-circuit current (Isc) in isolated frog skin and the induction of surface potentials in lipid bilayer membranes produced by the diuretic drug amiloride and a number of its chemical analogues was studied. The major conclusions of our study are: (a) The charged form of amiloride is the biologically active species. (b) Both the magnitude of Isc and the amiloride inhibitory effect are sensitive to the ionic milieu bathing the isolated skin, and these two features are modulated at separate and distinct regions on the transport site. (c) Amiloride is very specific in its inhibitory interaction with the Na+ transport site since slight structural modifications can result in significant changes in drug effectiveness. We found that substitutions at pyrazine ring position 5 greatly diminish drug activity, while changes at position 6 are less drastic. Alterations in the guanidinium moiety only diminish activity if the result is a change in the spatial orientation of the amino group carrying the positive charge. (d) Amiloride can bind to and alter the charge on membrane surfaces, but this action cannot explain its highly specific effects in biological systems.

Amiloride↗

PubMed2000

Prostasomes inhibit the NADPH oxidase activity of human neutrophils.

Prostasomes are particular lipid vesicles secreted by the prostate in human semen and involved in several physiological functions such as the improvement of sperm motility or immunomodulation. We have previously shown that they reduced the overall reactive oxygen species (ROS) production of seminal polymorphonuclear neutrophils (PMN). The present study was conducted to define the mechanism by which prostasomes inhibit the ROS production of blood and seminal PMN. The luminol chemiluminescence measuring total ROS production of blood PMN stimulated by either a phorbol ester (PMA) or a chemoattractant peptide, formyl-Met-Leu-Phe (fMLP) was significantly inhibited by prostasomes. The NADPH oxidase activity of the PMN was measured by 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1, 2-a]pyrazin-3-one (MCLA) chemiluminescence. Prostasomes inhibited the NADPH oxidase activity of blood or seminal PMN and increased the lag-phase of the enzyme after PMA stimulation. Prostasomes also inhibited significantly the NADPH oxidase activity of fMLP stimulated blood PMN, but the inhibition was not significant for seminal PMN. The lipid composition of blood PMN was analysed and compared to the lipid composition of prostasomes. This showed that prostasomes had a high cholesterol:phospholipid molar ratio and a high proportion of sphingomyelin. Together with the fact that prostasomes can rigidify the plasma membrane of blood PMN, these results led us to postulate that prostasomes inhibit the NADPH oxidase activity of PMN by lipid transfer from the prostasomes to the plasma membrane of the PMN.

Cholesterol↗

PubMed2001

The effects of lidocaine on superoxide production and p47 Phox translocation in opsonized zymosan-activated neutrophils.

UNLABELLED: Superoxide is generated by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase that exists in the cell membrane of neutrophils and contains p47 phox in the enzyme complex. Superoxide is closely related to various diseases, including infection, myocardial infarction, and aspiration pneumonia. Therefore we performed this study to establish how lidocaine acts on NADPH oxidase. We examined the effects of lidocaine on superoxide production in neutrophils using the method of 2-methyl-6-phenyl-3,7-dihydro [1,2-a] pyrazin-3-one (CLA phenyl)-dependent chemiluminescence activated by opsonized zymosan (OZ). Treatment with lidocaine 15 microM suppressed OZ-activated CLA phenyl-dependent chemiluminescence by approximately 40% compared with that of OZ only-activated neutrophils. It was further demonstrated that the suppressive effect of lidocaine on superoxide production was dependent on the concentration of lidocaine. Translocation of p47 phox from the cytosol to the cell membrane was studied using immunoblot analysis with a polyclonal anti-p47 phox antibody. Lidocaine suppressed OZ-induced p47 phox translocation in a dose-dependent manner. Our results suggest that suppression of superoxide production by a therapeutic dose of lidocaine correlates strongly with suppression of p47 phox translocation. IMPLICATIONS: We report on the effects of lidocaine on superoxide production in opsonized zymosan-activated neutrophils. Lidocaine suppresses superoxide production in a dose-dependent manner. This suppression correlates strongly with the suppression of translocation of p47 phox, a new subunit of NADPH-oxidase.

Adult↗

PubMed1998

Phosphodiesterase III and V inhibitors on pulmonary artery from pulmonary hypertensive rats: differences between early and established pulmonary hypertension.

Milrinone and 6-bromo-8(methylamino)imidazo[1,2a]pyrazine-2-carbonitrile [SCA40; phosphodiesterase (PDE) III inhibitors], zaprinast (PDE V inhibitor), and 3-isobutyl-1-methyl xanthine (IBMX; nonselective PDE inhibitor) were examined on main pulmonary arteries from control rats and rats exposed to hypoxia (10% O2; 1 or 4 weeks) to induce pulmonary hypertension. Each drug fully relaxed preparations precontracted submaximally with phenylephrine. In the absence of endothelium or the presence of the nitric oxide synthase inhibitor, L-NAME, responses to zaprinast, but not the other drugs, were reduced but not abolished. The potencies [negative log median effective concentration (EC50)] of the drugs in 4-week hypoxic rats (established pulmonary hypertension; zaprinast, 5.60; milrinone, 5.64; SCA40, 6.41; IBMX, 5.38) were not different from corresponding control values (6.05; 5.88; 6.65; 5.64) but in early pulmonary hypertension (1-week hypoxic rats), all except IBMX had reduced potency. The potency of the adenylate cyclase activator, forskolin, was reduced in arteries from both groups of rats. In early, but not established, pulmonary hypertension, arteries had inherent tone, spontaneous contractions, and diminished endothelial function. In established, but not early, pulmonary hypertension, arteries had increased overall contractile ability. It is concluded that (a) PDE V inhibitors require cyclic guanosine monophosphate (cGMP) produced by endothelial nitric oxide for optimal effect, (b) the potencies of PDE III and V inhibitors are not compromised in established pulmonary hypertension, and (c) data on pulmonary vascular function obtained in 1-week hypoxic rats do not necessarily reflect data in rats exposed to hypoxia for longer periods.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Detection of superoxide free radicals in rats with acute pancreatitis.

To study the importance of oxygen-derived free radicals in acute pancreatitis, an experimental study of in vivo detection of superoxide free radicals (O2-) was performed using rats. Using a new chemiluminescence probe (2-methyl-6-[p-methoxyphenyl]-3,7-dihydro-imidazol[1,2-1]pyrazin- 3-one; MCLA; a Cypridina luciferin analogue) and a highly sensitive photon counting system, O2- from the pancreatic surface of rats with experimental acute pancreatitis induced by 180 micrograms cerulein/kg was detected. The time course of MCLA-dependent luminescence suggested that O2- production began 2-3 h after cerulein injection and then decreased gradually. Superoxide free radical production in the pancreas of rats with cerulein-induced acute pancreatitis was confirmed using MCLA-dependent chemiluminescence. This new method allows direct observation of the behavior of oxygen-derived free radicals.

Acute Disease↗

PubMed2000

In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics.

The effects of serotonin (5-HT) receptor ligands on the MK 212 (6-chloro-2[1-piperazinyl]pyrazine) discriminative stimulus and quipazine-induced head twitches were studied in rats. 5-HT1A (8-OH-DPAT) and preferential 5-HT2A (DOI) receptor agonists did not generalize to the discriminative stimulus. The 5-HT2B/2C-receptor antagonist, SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole), and the 5-HT2A/2C-receptor antagonist, ritanserin, acted as potent antagonists, whereas the 5-HT2A-receptor antagonist, MDL 100.151 ([(+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4- piperidine-methanol), produced minor and inconsistent inhibition. SB 206553 was a weak antagonist against quipazine-induced head twitches, whereas MDL 100.151 and ritanserin were potent antagonists. This suggests that the MK 212 discriminative stimulus is mediated by 5-HT2C receptors, while quipazine-induced head twitches are mediated primarily by 5-HT2A receptors. The effects on quipazine-induced head twitches were comparable to previously published effects on the DOI discriminative stimulus. 5-HT2A- and 5-HT2C-receptor antagonistic potencies of clozapine, olanzapine, risperidone, sertindole and ziprasidone were compared in the same models. Clozapine showed similar potencies in both models, while sertindole, olanzapine and risperidone inhibited quipazine-induced effects more potently than the MK 212 discriminative stimulus. Ziprasidone exerted a minor preference for 5-HT2A- compared to 5-HT2C-receptor-mediated effects. The ratio between in vivo inhibitory potencies at 5-HT2A and 5-HT2C receptors did not correlate with corresponding ratios from in-vitro affinity and ex-vivo occupancy studies in the literature.

Animals↗

PubMed2004

Anxiogenic effects in the rat elevated plus-maze of 5-HT(2C) agonists into ventral but not dorsal hippocampus.

The effect of the non-selective 5-HT2C receptor agonist trifluoromethyl-phenylpiperazine (TFMPP, 0.75, 1.5 and 3.0 microg) and the preferential 5-HT2C agonist 6-chloro-2(1-piperazinyl)pyrazine (MK-212, 0.1, 0.3 and 1.0 microg) microinjected into the ventral or dorsal hippocampus was investigated in anxiety measures of rats exposed to the elevated plus-maze test. Ventral hippocampal (VH) microinjections of the 0.75 or 1.5 microg doses of TFMPP reduced open-arm exploration without affecting the number of closed-arm entries, indicating a selective anxiogenic profile. The highest dose (3.0 microg) reduced open- and closed-arm entries, suggesting interference in locomotor activity. The 0.1 microg dose of MK-212 also caused a selective anxiogenic effect when microinjected into the ventral hippocampus, without disturbing locomotor activity. Microinjections of the two higher doses of MK-212 (0.3 or 1.0 microg) into the ventral hippocampus led to a decrease of exploration in both arms of the maze. In contrast to the anxiogenic effect observed in the VH, neither TFMPP nor MK-212 significantly changed anxiety measures when microinjected into the dorsal hippocampus. These results suggest that activation of 5-HT2C postsynaptic receptors located in the ventral, but not in the dorsal, hippocampus play an important role in anxiety triggered by the elevated plus-maze test.

Animals↗