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PubMed2000

Interaction of a series of draflazine analogues with equilibrative nucleoside transporters: species differences and transporter subtype selectivity.

The equilibrative nucleoside transporters of mammalian cells play an important role in the regulation of extracellular adenosine concentrations, and inhibition of these transporters potentiates the biological effects of adenosine. Two subtypes of equilibrative transporters have been defined by their differential sensitivities to inhibition by nitrobenzylthioinosine (NBMPR; es/ENT1, sensitive; ei/ENT2, insensitive). In addition, significant species differences have been noted in es/ENT1 transporter affinity for a subset of inhibitors including draflazine and dipyridamole. Draflazine and a series of 15 chemically related compounds were compared for their abilities to: (a) inhibit the binding of [3H]NBMPR to the es/ENT1 transporter in mouse Ehrlich cell and human erythrocyte membranes, and (b) inhibit the es/ENT1 and ei/ENT2 transporter-mediated uptake of [3H]uridine in Ehrlich cells. Compounds within this series represented over a 1000-fold range of affinities for the es/ENT1 and ei/ENT2 transporters with subtype selectivities (ENT1/ENT2) ranging from 370 for R70527 to 0.17 for soluflazine. Five other analogues were identified, in addition to soluflazine, that had significantly higher affinity for the ei/ENT2 transporter compared with es/ENT1. Structure activity analyses of these data identified the requirement of a hydrophobic group connected to a 2-aminocarbonyl piperazine by a 5-carbon chain for high-affinity interactions with es/ENT1. This hydrophobic moiety was not as important for ei/ENT2 affinity and, in contrast to es/ENT1, a shorter alkyl chain enhanced binding to ei/ENT2. These draflazine analogues also varied in their differential affinities for mouse vs. human es/ENT1 transporters, and the degree of species discrimination was strongly dependent on the position of the aminocarbonyl group on the piperazine ring. This information, combined with structural data derived from molecular studies with ENT1 and ENT2 recombinant proteins, should guide further development of subtype-selective inhibitors of the equilibrative nucleoside transporters.

Animals↗
PubMed2003

Quantitative enantiomeric analysis of chlorcyclizine, hydroxyzine, and meclizine by capillary electrophoresis.

A simple capillary zone electrophoresis method was developed for the quantitative enantiomeric analysis of piperazine antihistamines with teratogenic suspicion in animals. Enantioseparation of chlorcyclizine, hydroxyzine, and meclizine was performed in glycine buffer (0.6 mol L(-1); pH 3.00) with sulfated beta-cyclodextrin (5 mg mL(-1)) as a chiral selector; and the separated drugs were monitored by ultra-violet detector. The lower quantitation of the individual enantiomer is attainable at 10 micro mol L(-1), using an achiral piperazine drug (cyclizine) as internal standard. The method is simple and rapid with a short run time (<5 min) for the analysis of chlorcyclizine, hydroxyzine or meclizine enantiomers.

Animals↗
PubMed2006

Identification of metabolites produced from N-phenylpiperazine by Mycobacterium spp.

Mycobacterium sp. 7E1B1W and seven other mycobacterial strains known to degrade hydrocarbons were investigated to determine their ability to metabolize the piperazine ring, a substructure found in many drugs. Cultures were grown at 30 degrees C in tryptic soy broth and dosed with 3.1 mM N-phenylpiperazine hydrochloride; samples were removed at intervals and extracted with ethyl acetate. Two metabolites were purified from each of the extracts by high-performance liquid chromatography; they were identified by mass spectrometry and (1)H nuclear magnetic resonance spectroscopy as N-(2-anilinoethyl)acetamide and N-acetyl-N'-phenylpiperazine. The results show that mycobacteria have the ability to acetylate piperazine rings and cleave carbon-nitrogen bonds.

Magnetic Resonance Spectroscopy↗
PubMed2006

Prolonged treatment with ligands affects ligand binding to the human serotonin(1A) receptor in Chinese hamster ovary cells.

1. The serotonin(1A) receptors are members of a superfamily of seven transmembrane domain receptors that couple to G-proteins, and appear to be involved in several behavioral and cognitive functions. 2. We monitored the effect of prolonged treatment of the human serotonin(1A) receptor expressed in Chinese hamster ovary (CHO) cells with pharmacologically well-characterized ligands on its binding to the agonist 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT) and antagonist 4-(2'-methoxy)-phenyl-1-[2'-(N-2''-pyridinyl)-p-fluorodobenzamido]ethyl-piperazine (p-MPPF). 3. Our results indicate that prolonged treatment with the specific agonist (8-OH-DPAT) differentially affects subsequent binding of the agonist and antagonist to the receptor in a manner independent of receptor-G-protein coupling. Importantly, our results show that prolonged treatment with the commonly used antagonist p-MPPF, and its iodinated analogue 4-(2'-methoxy)-phenyl-1-[2'-(N-2''-pyridinyl)-p-iodobenzamido]ethyl-piperazine (p-MPPI), which have earlier been reported to display similar binding properties to serotonin(1A) receptors, induces significantly different effects on the ligand binding function of serotonin(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

The dopamine transporter and cytochrome P45OIID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins.

Two [3H]GBR-12935 binding proteins, identified as the dopamine transporter and cytochrome P45OIID1, were solubilized in digitonin from canine striatal membranes, and were resolved following wheat germ agglutinin (WGA)-lectin column chromatography. Protein adsorbed to and specifically eluted from WGA-lectin with N-acetylglucosamine displayed saturable, high affinity (KD approximately 3 nM), and sodium-dependent binding of [3H]GBR-12935, which was inhibited in a concentration-dependent and stereoselective manner by dopamine uptake blockers and substrates with a pharmacological profile indicative of the dopamine uptake site. Protein not adsorbed to WGA-lectin also bound [3H]-GBR-12935 with high affinity (approximately 7 nM), in a sodium-independent manner, and was insensitive to classical dopamine uptake blockers and substrates such as mazindol or dopamine, corresponding to the so-called "piperazine acceptor" site seen in native membranes. [3H]GBR-12935 binding to this latter protein was, however, inhibited by various compounds with a pharmacological profile indicative of a form of cytochrome P450 designated P45OIID1 (debrisoquine/sparteine monooxygenase) with the following rank order of inhibitory potency: GBR-12909 greater than budipine greater than alpha-lobeline greater than quinidine greater than alpha flupenthixol greater than SKF-525A greater than sparteine greater than quinine. Ki values obtained for inhibition of [3H]-GBR-12935 binding to neuronal WGA passthrough fractions by these drugs correlate well with their respective Ki values for liver P45OIID1 activity. Western blotting and immunoprecipitation analysis with rabbit anti-rat P45OIID1 antibody also supported the identity of the mazindol-insensitive [3H]GBR-12935 binding site (or piperazine acceptor site) as P45OIID1. Furthermore, a [3H]GBR-12935 binding protein with pharmacological and immunological characteristics similar to those of P45OIID1 was solubilized from both bovine and human liver membranes, and GBR-12909 was found to be a potent competitive inhibitor (Ki approximately 100 nM) of sparteine monooxygenase activity in human liver microsomes. These data clearly indicate that [3H]GBR-12935 and its analogs display similar affinities for both the dopamine transporter and neuronal P45OIID1, and that this radioligand may be a useful probe of P45OIID1 activity in brain and liver. The exact molecular and functional association (if any) between these two distinct binding protein populations remains to be established; however, it is tempting to speculate that P45OIID1 is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells.

Animals↗
PubMed1983

Mode of insertion of miconazole, ketoconazole and deacylated ketoconazole in lipid layers. A conformational analysis.

The conformation of three imidazole derivatives, miconazole, ketoconazole and deacylated ketoconazole (R 39 519) inserted in a lipid layer was calculated using a procedure of conformational analysis. For each imidazole derivative all probable conformers were inserted into a dipalmitoyl phosphatidylcholine (DPPC) monolayer. Miconazole maintains its two dichlorophenyl groups in the hydrophobic phase whereas the imidazole moiety is orientated in the hydrophilic phase. Ketoconazole orientates its dichlorophenyl group in the hydrophobic phase whereas its acylated piperazine moiety is orientated towards the hydrophobic region. Deacylation inverses completely the orientation of the compound. The most probable conformer of R 39 519 is inserted in the lipid layer with its piperazine moiety orientated towards the aqueous phase. The inversion increases the area occupied per drug molecule from 30 A2 for ketoconazole to 90 A2 for R 39 519 equal to the mean area occupied per miconazole molecule and higher than that occupied per DPPC molecule (60 A2). Such a conformation should result in a destabilizing effect of miconazole and R 39 519; this was proved using differential scanning calorimetry.

Antifungal Agents↗
PubMed1986

The effects of BM 15.766, an inhibitor of 7-dehydrocholesterol delta 7-reductase, on cholesterol biosynthesis in primary rat hepatocytes.

The effect of the piperazine derivative BM 15.766 (4-(2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) on the biosynthesis of sterols was investigated in adult rat hepatocytes in primary monolayer culture. The substance led to a dose-dependent reduction of cholesterol in the serum of various species of animals such as rat, dog and marmoset. BM 15.766 showed a dose-dependent action on the incorporation of 14C-acetate in neutral, nonsaponifiable lipids. The inhibition of the overall incorporation was 10-12% (10(-5) M). No inhibition was observed in the hepatocytes over the entire dose range of 10(-8) M to 2 X 10(-5) M, while the release of the neutral lipids from the hepatocytes into the culture medium was reduced by up to 40%. The biosynthesis of cholesterol could be reduced by more than 90%. Simultaneously, 7-dehydrocholesterol levels rose in the cells and, to a less marked extent, in the medium. This can be interpreted as an indication that 7-dehydrocholesterol is incorporated into the cell membrane, which results in a lower release of 7-dehydrocholesterol into the medium in comparison with controls. The site of attack is the inhibition of the delta 5.7-sterol delta 7-reductase. The formation of desmosterol and cholestatrienol as well as other 7-dehydrocholesterol precursors could also be demonstrated. After longer incubation, there was an additional accumulation of squalene and lanosterol with simultaneous reduction of 7-dehydrocholesterol by BM 15.766, whereas the total 14C-acetate incorporation in neutral lipids was increased.

Acetates↗
PubMed1995

Translocation of dopamine and binding of 2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane (WIN 35,428) measured under identical conditions in rat striatal synaptosomal preparations. Inhibition by various blockers.

Translocation of [3H]dopamine and binding of 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)[3H]-tropane ([3H]WIN 35,428) were measured in crude synaptosomal preparations from rat striatum under identical conditions of assay buffer (phosphate-Krebs) and temperature (25 degrees). [3H]Dopamine uptake as a function of time was close to linear for at least 8 min, whereas [3H]WIN 35,428 binding had reached equilibrium within 1 min and remained at its plateau value for at least 20 min. The following inhibitors were tested in uptake and binding assays run in parallel with the same synaptosomal preparation: cocaine, WIN 35,428, benztropine, nomifensine, mazindol, methylphenidate, N-[1-(2-benzo[b]-thiophenyl)cyclohexyl]piperidine (BTCP), Lu 19-005 (Indatraline), 1-(2-(di(4-fluorophenyl)-methoxy)-ethyl)-4-(3-phenyl-2-propyl)piperazine (GBR 12909), 1-(2-(diphenylmethoxy)-ethyl)-4-(3-phenyl-2-propyl)piperazine (GBR 12935) and 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo [1,2-a]quinoxaline (CGS 12066B). When present together with [3H]dopamine or [3H]WIN 35,428 for 8 min, the observed binding IC50 values were generally higher (average 1.4-fold) than the uptake IC50 values, with a significant y-axis intercept in linear regression analysis of binding on uptake IC50. For slowly equilibrating inhibitors, estimates of uptake IC50 values were overestimates, and relatively lower values were obtained by monitoring [3H]dopamine uptake for 1 min only during the last minute of the 8-min presence of inhibitor; under these conditions, binding over uptake IC50 ratios were on the average 2.3. Kinetic calculations, taking into account both radioligand and inhibitor equilibration kinetics, indicated that the latter comparison between binding and uptake measurements was most relevant, and suggested the involvement of complexities beyond simple competitive inhibition of dopamine transport, such as different binding domains for substrate and blocker recognition, or spare receptors for blockers. The present data indicate that binding over uptake IC50 ratios should be interpreted with caution, depending on the experimental conditions used to measure these ratios.

Animals↗
PubMed1991

Quantitative autoradiography of the dopamine uptake complex in rat brain using [3H]GBR 12935: binding characteristics.

The dopamine uptake complex was examined in the rat central nervous system using [3H]GBR 12935 and in vitro quantitative autoradiography to determine all binding data. [3H]GBR 12935 labels two unique binding sites, the dopamine uptake complex and a piperazine acceptor site. These two sites differ in their pharmacologic properties, anatomical distributions, densities, and response to lesions. Using appropriate binding conditions, [3H]GBR 12935 can be used to specifically label the dopamine uptake complex. [3H]GBR 12935 labeled a single binding site with characteristics of the dopamine uptake complex when mazindol (25 microM) was used as a blank. The specific binding and autoradiographic appearance of [3H]GBR 12935 to the dopamine uptake complex was improved by including trans-flupentixol (0.75 microM) to displace binding to a previously described piperazine acceptor site, recently determined to be a site on cytochrome P450IID1. Binding was saturable and reversible to the dopamine uptake complex. The equilibrium dissociation constant (1.4 +/- 0.7 nM), maximal number of binding sites (6.0 +/- 1.3 pmol/mg protein), and Hill coefficient (1.1 +/- 0.1) of [3H]GBR 12935 in rat striatum using mazindol to define non-specific binding was not significantly altered by the inclusion of trans-flupentixol (0.75 microM). Using GBR 12909 as a blank produced a greater maximal number of binding sites (8.4 +/- 2.3 pmol/mg protein), but no significant difference in the equilibrium dissociation constant (1.6 +/- 0.3 nM) or Hill coefficient (1.1 +/- 0.1). A series of drugs that bind to the dopamine uptake complex displaced [3H]GBR 12935 in a rank order consistent with other binding and behavioral studies of this complex. The rank order of these drugs was GBR 12909 greater than mazindol greater than nomifensine greater than benztropine greater than desipramine greater than amphetamine greater than dopamine; all these drugs displayed a Hill coefficient near one and were best modeled as a single site. Cocaine and WIN 35,428 (a cocaine congener) were unique in their competition for [3H]GBR 12935 binding, displaying biphasic curves, low Hill coefficients, and were best modeled as two site fits. Lesioning of the dopaminergic median forebrain bundle resulted in a dramatic loss of the dopamine uptake complex in the striatum, nucleus accumbens, olfactory tubercle, and substantia nigra. Other dopaminergic projection areas were decreased to a lesser extent. Striatal ibotenate lesions did not decrease the density of the dopamine uptake complex, despite a large decrease in the dopamine D1 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Cortically evoked excitatory synaptic transmission in the cat red nucleus is antagonised by D-AP5 but not by D-AP7.

Extracellular recordings were made from magnocellular red nucleus neurons (mRN) in alpha-chloralose (50 mg/kg, iv.) anaesthetised cats. Iontophoretically applied N-methyl-D-aspartate (NMDA) excited the neuronal firing which was antagonised by 4 selective NMDA receptor antagonists: 2-amino-5-phosphonopentanoate (AP5), 2-amino-7-phosphonoheptanoate (AP7), RS-4-(phosphonomethyl) piperazine-2-carboxylic acid (PMPC) and R-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP), whereas AMPA responses were uneffected. Monosynaptic excitatory responses were produced by stimulation of the sensorimotor cortex. These responses were reduced and often abolished by AP5 and PMPC but not by AP7 or CPP. It is postulated that two NMDA receptor subtypes exist on mRN neurones.

2-Amino-5-phosphonovalerate↗
PubMed1994

5-HT1A receptor-mediated inhibition of lateral vestibular nucleus neurons projecting to the abducens nucleus.

Electrophysiological studies were performed using cats anesthetized with alpha-chloralose, to elucidate the 5-hydroxytryptamine (5-HT) receptor subtypes involved in the 5-HT-induced inhibition of the lateral vestibular nucleus (LVN) neurons projecting to or through the abducens nucleus. The effects of 5-HT receptor subtype agonists and antagonist were examined in polysynaptic neurons activated by stimulation of the ipsilateral abducens nucleus (IAN) antidromically, since these neurons are sensitive to 5-HT as shown in our previous study. Iontophoretic application of 5-HT and 8-hydroxy-2-(di-n-propylamino)tetrain (8-OH-DPAT), a selective 5-HT1A agonist, inhibited orthodromic spikes elicited by vestibular nerve stimulation in the majority of polysynaptic neurons activated by stimulation of ipsilateral IAN antidromically. There was a good correlation between the effects of 5-HT and 8-OH-DPAT. Iontophoretically applied 5-HT and 8-OH-DPAT also inhibited glutamate-induced firing in these neurons. Simultaneous application of 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190), a 5-HT1A agonist/antagonist, significantly antagonized the 8-OH-DPAT-induced inhibition of glutamate-induced firing, although NAN-190 alone also caused weak suppression of glutamate-induced firing. Microiontophoretically applied 1-(3-chlorophenyl)piperazine (mCPP), a 5-HT1B agonist inhibited the orthodromic spike elicited by vestibular nerve stimulation and glutamate-induced firing in only a small number of the LVN neurons. 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 agonist, rarely affected these neurons. We postulate that postsynaptically located 5-HT1A receptors are mainly involved in the 5-HT-induced inhibition of polysynaptic neurons projecting in the region of the IAN.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin.

Fluoxetine, a serotonin (5-HT) reuptake inhibitor, has been documented to exert a protective action against convulsive seizures in animal models, when administered either systemically, or focally into substantia nigra. It is likely that the mechanism of anticonvulsant action of fluoxetine is due to an enhancement of endogenous 5-HT transmission. To evaluate this possibility in the context of the anticonvulsant action of intranigral fluoxetine, we examined the influence of 5-HT-mediated transmission in substantia nigra on seizure susceptibility in a rat model of focally evoked complex partial seizures. In addition to fluoxetine (3.5 nmol), we found that the directly acting 5-HT receptor agonists, 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (10 nmol), 1-(3-chlorophenyl)piperazine (m-CPP) (7.4 nmol), gepirone (70 nmol) and 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) (10 nmol), when microinjected bilaterally into substantia nigra, protected rats from limbic motor seizures evoked focally from area tempestas, an epileptogenic site in the deep rostral piriform cortex. This indicates that multiple 5-HT receptor subtypes in substantia nigra may contribute to seizure regulation. Consistent with this, the 5-HT antagonist, metergoline, partially reversed the anticonvulsant action of intranigral fluoxetine. Depletion of endogenous 5-HT, by pretreatment with parachlorophenylalanine (PCPA), completely prevented the anticonvulsant action of intranigral fluoxetine, without modifying the anticonvulsant effect of intranigral TFMPP. These findings support the proposal that the anticonvulsant action of fluoxetine in substantia nigra is due to an enhancement of the synaptic action of endogenous 5-HT in substantia nigra which in turn is mediated via multiple 5-HT receptors. Endogenous 5-HT transmission in substantia nigra is therefore capable of limiting the development and propagation of seizure activity generated in limbic circuits.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

5-HT1B agonists induce anorexia at a postsynaptic site.

Ru 24969 and two other putative 5-HT1B agonists 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl) phenyl]piperazine (TFMPP) and RU 24969 dose-dependently decreased food intake over 4 h (and in the case of RU 24969 also over 24 h) in free-feeding male Sprague-Dawley rats. Decreasing the doses of the agonists below the range eliciting anorexia did not cause hyperphagia. The anorexic effect of RU 24969 over 4 h was antagonised by metergoline, (-)pindolol and (+/-)cyanopindolol, but not by ketanserin, spiperone or haloperidol. Metergoline and (+/-)cyanopindolol also antagonised the anorexic effect of RU 24969 over 24 h. This data is consistent with an action mediated by 5-HT1B receptors. Locomotor activity induced by RU 24969 was markedly antagonised by haloperidol despite its lack of effect on the anorexic response. Persistence of the anorexic effect of RU 24969 after p-chlorophenylalanine (pCPA) pretreatment suggests that 5-HT1B agonists induce anorexia at a postsynaptic 5-HT receptor.

Animals↗
PubMed1988

A pharmacological analysis of the rat spinal cord serotonin (5-HT) autoreceptor.

The pharmacological characteristics of the presynaptic 5-HT receptor associated with the modulation of 5-HT release were investigated in a preparation of rat spinal cord synaptosomes (nerve terminals) superfused with a Tris-buffered Krebs solution containing fluoxetine (1 microM). The 5-HT receptor agonists serotonin (1-100 nM), lysergic acid diethylamide (10 nM-1 microM) and the 5-HT1B receptor agonists 1-(m-trifluoromethylphenyl)piperazine (100 nM-1 microM) and 1-(m-chlorophenyl) piperazine (100 nM-3 microM) concentration dependently decreased [3H]5-HT release, while 8-hydroxy-2-(di-n-propylamino)tetralin, a selective 5-HT1A receptor agonist, was inactive. The actions of the effective agonists were reversed by quipazine, an antagonist with high affinity for 5-HT1B binding sites, but not by spiperone, a 5-HT1A receptor antagonist. Furthermore, mesulergine, a 5-HT1C receptor antagonist was ineffective in reversing the action of 5-HT on [3H]5-HT release. These data indicate that the rat spinal cord nerve terminal autoreceptor has characteristics similar to the 5-HT1B binding site.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists.

1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (0.1-1.0 mg/kg) reduce total interaction time in a rat social interaction test under low light familiar conditions and its following components; grooming, following, crawling over, fighting, sniffing. Locomotion was only reduced by the highest dose of mCPP. mCPP also reduced activity in the light but not total locomotion in a light/dark transition test. These results suggest that mCPP (and TFMPP) are anxiogenic but not sedative in these tests. The effect of mCPP on social interaction was blocked by three antagonists which share a high affinity for 5-HT1C and 5-HT2 receptors: mianserin, cyproheptadine and metergoline but not by the 5-HT2 antagonists ketanserin or ritanserin or the 5-HT1A and 5-HT1B antagonists cyanopindolol and (-)-propranolol. It was prevented by a low (0.05 mg/kg) but not by a high (1.0 mg/kg) dose of ICS 205,930 a specific 5-HT3 antagonist reported to be anxiolytic at low doses. It was also prevented by chronic pretreatment with the anxiolytic drug chlordiazepoxide. These results argue for an anxiogenic action of mCPP mediated by 5-HT1C receptors. Since the chronic chlordiazepoxide pretreatment did not prevent the hypolocomotion or hypophagia induced by mCPP at high dosage (5 mg/kg) these latter effects are unlikely to be secondary to anxiety.

Animals↗
PubMed1990

Effects of the 5-HT1C/5-5-HT2 receptor agonists DOI and alpha-methyl-5-HT on plasma glucose and insulin levels in the rat.

Administration of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI, 0.125-2.0 mg/kg i.v.) triggered dose-dependent increases in plasma glucose; plasma insulin levels remained unchanged. Pretreatment with the 5-HT1C/5-HT2 receptor antagonists LY 53857, ritanserin, or the mixed 5-HT2/alpha 1-adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT1C receptor agonists/5-HT2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-trifluoromethyl)phenyl)piperazine level (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The alpha 2-adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, Whilst the alpha 1-adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT1C/5-HT2 receptor agonist alpha-methyl-5-HT (0.5-1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished alpha-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT2 receptors, but not 5-HT1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT2 receptors may affect glycemia.

Amphetamines↗
PubMed1990

Chronic but not acute antidepressants interfere with serotonin (5-HT1B) receptors.

Eight days of isolation induced in mice a social behavioral deficit responsive to the serotonin agonists, TFMPP (1-(m-trifluoromethylphenyl)piperazine), m-CPP (1-(3-chlorophenyl)piperazine), RU 24969. These drugs are not specific for one subtype of serotonin receptors but share the property of being able to stimulate 5-HT1B receptors. They exert their effects in this test through this receptor. Fluoxetine and phenelzine were behaviorally inactive and did not impair the TFMPP effect when given acutely. On the contrary, the chronic administration of these two antidepressant drugs significantly antagonized the TFMPP effect. These results demonstrate a link between two antidepressant drugs and a function of 5-HT1B receptors. The lack of effect of acute versus chronic treatments suggests the involvement of 5-HT1B receptors in the therapeutic effect of these drugs.

Animals↗
PubMed1990

Agonist action at 5-HT1C receptors facilitates 5-HT1A receptor-mediated spontaneous tail-flicks in the rat.

In rats lightly restrained in plastic cylinders, subcutaneous administration of the selective, high efficacy 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), induced spontaneous tail-flicks, that is, tail-flicks in the absence of extraneous stimulation. The putative 5-HT1B receptor agonist, CGS 12066B, the mixed 5-HT1B/1C receptor agonists, 1-((3-(trifluoromethyl)phenyl]piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP), the 5-HT1C/2 receptor agonist, [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT1B/1C/2 receptor agonist, quipazine, did not, in contrast, elicit tail-flicks when applied alone. However, TFMPP, mCPP, DOI and quipazine, but not CGS 12066B, each potentiated the action of 8-OH-DPAT. Further, in the presence of TFMPP, mCPP and DOI, the dose-response curve for the induction of tail-flicks by 8-OH-DPAT was both steeper and shifted to the left. Tail-flicks induced by another high efficacy 5-HT1A receptor agonist, lisuride, were also enhanced by TFMPP, mCPP and DOI. The 5-HT1A receptor partial agonists, buspirone and (+/-)-flesinoxan, evoked tail-flicks only in the presence of TFMPP, mCPP or DOI. The mixed 5-HT1C/2 receptor antagonists, ritanserin and ICI 169,369, did not modify the action of 8-OH-DPAT alone but abolished the potentiation of 8-OH-DPAT-induced tail-flicks by DOI and TFMPP. Further, the selective 5-HT1A receptor antagonist, BMY 7378, blocked tail-flicks induced by both 8-OH-DPAT alone and 8-OH-DPAT plus DOI or TFMPP. A common property of those drugs potentiating 8-OH-DPAT-induced tail-flicks is an agonist action at 5-HT1C receptors and the data indicate that it is this mechanism which underlies the facilitation of tail-flicks.

8-Hydroxy-2-(di-n-propylamino)tetralin↗