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PubMed2006

Mechanism of DNA damage induced by bromate differs from general types of oxidative stress.

A representative reactive oxygen species (ROS), hydroxyl radical (*OH), is a highly reactive species and induces DNA backbone breakage. *OH also oxidizes every DNA base. The interaction of *OH with guanine leads to the generation of not only piperidine-resistant 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) but also various piperidine-labile products. On the other hand, potassium bromate (KBrO3) induces specific formation of 8-oxodG in the presence of SH compounds, such as glutathione (GSH) and cysteine (Cys). GSH/Cys reduces KBrO3 (BrO3-) to BrO2, which abstracts one electron from guanine. The one-electron oxidation of guanine may yield cation radicals followed by the reaction with a water molecule, leading to 8-oxodG formation. Therefore, mechanism of bromate-induced oxidative DNA damage is different from general types of oxidative stress such as *OH.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Tachykinin NK(3) receptor agonists induced microvascular leakage hypersensitivity in the guinea-pig airways.

Microvascular leakage hypersensitivity is a main component of neurogenic inflammation and of tachykinin effects. The aim of this study was to examine the ability of neurokinin B and of the tachykinin NK(3) receptor agonists, [MePhe(7)]neurokinin B or senktide, to potentiate when given by aerosol the microvascular leakage induced by histamine in guinea-pig airways and to compare their effects to those of tachykinin NK(1) (substance P, [Sar(9),Met(O(2))(11)]substance P) or tachykinin NK(2) (neurokinin A, [betaAla(8)]neurokinin A (4-10)) receptor agonists. Guinea-pigs were pretreated successively for 10 min with aerolized salbutamol and phosphoramidon; 15 min later, they were exposed for 30 min to an aerosolized solution of tachykinin receptor agonists; 24 h later, the animals were anaesthetized and vascular permeability was quantified by extravasation of Evans blue dye. Neurokinin B, [MePhe(7)]neurokinin B and senktide (3 x 10(-6)-3 x 10(-5)M) induced a potentiation of the effects of histamine on the vascular permeability in the trachea and main bronchi. Compared to other tachykinin NK(1) and NK(2) receptor agonists, the order of potency was: senktide>neurokinin B=[Sar(9),Met(O(2))(11)]substance P=[betaAla(8)]neurokinin A (4-10)=[MePhe(7)]neurokinin B>neurokinin A>substance P. The potentiation by [MePhe(7)]neurokinin B of histamine-induced microvascular leakage was abolished by the tachykinin NK(1) receptor antagonist SR140333 ([(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidin-3-yl]etyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride]) or the tachykinin NK(3) receptor antagonists SR 142801 ([(R)-(N)-(1-(3-(l-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide]) and SB 223412 ([(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide]). In conclusion, these results suggest that tachykinin NK(3) receptors might be involved in the potentiation of histamine-induced increase in microvascular permeability.

Aerosols↗
PubMed2003

Pharmacological evidence for a correlation between hippocampal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils.

Global ischemia, induced in Mongolian gerbils by bilateral occlusion of the carotid arteries for 5 min, produced a significant increase in locomotor activity at 1 day post-occlusion and a severe loss of hippocampal CA1 neurons at 4 days post-occlusion. To explore the pharmacological relationship between ischemia-induced hypermotility and CA1 cell death in the hippocampus, we evaluated the efficacy of diverse classes of putative neuroprotective agents for preventing hypermotility and delayed neuronal death. Administration of any drug 30 min before global ischemia dose-dependently, and with similar potency, ameliorated both hippocampal delayed neuronal death and locomotor hyperactivity, with a rank order: tacrolimus (FK506)>nizofenone>clonindine>dizocilpine (MK-801)>6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K)>phencyclidine>pentobarbital>2-(4-(p-fluorobenzoyl)-piperidin-1-yl)-2'-acetonaphthone hydrochloride (E-2001)>cis-(+/-)-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755)>3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U-50,488H)>piroxicam>eliprodil>vinpocetine. Furthermore, potencies of the protective effect on delayed neuronal death and inhibitory effects on hypermotility were closely correlated (r=0.98). These results suggest that post-ischemic CA1 injury and hypermotility share common mechanisms, and further imply that it is possible to predict the neuroprotective efficacy of drugs more easily by examining the inhibitory effects on post-ischemic hypermotility in global ischemia model in gerbils.

Animals↗
PubMed1996

Peripheral effects of three novel non-peptide tachykinin NK1 receptor antagonists in the anaesthetized rat.

Three novel non-peptide tachykinin NK1 receptor antagonists were assessed on the transient fall in mean arterial blood pressure and the salivation induced by i.v. substance P (0.65 nmol/kg) in the urethane-anaesthetized rat. LY303241 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- phenylpiperazin-1-yl)acetyl)amino]propane), LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(++ +piperidin-1 -yl)piperidin-1-yl)acetyl)amino]propane) and LY306740 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4 -cyclohexylpiperazin-1-yl)acetyl)amino]propane) (65 nmol-9 micromol/kg i.v.; 5 min earlier) inhibited both the vasodepressor and salivary responses to substance P in a dose-dependent manner. LY303241 and LY306740 were more potent in inhibiting the vascular response to substance P while LY303870 was more potent in inhibiting the salivary response. LY303870 and LY306740 were devoid of direct effects while LY303241 decreased blood pressure and heart rate for 1 and 10 min, respectively. The antagonists act in a stereoselective and specific manner since the opposite (S) enantiomers of LY303870 (LY306155) and LY306740 (LY307679) failed to block the effects of substance P. In addition, LY303241, LY303870 and LY306740 neither affected the hypotension and the salivation induced by carbachol nor the increases in mean arterial pressure and heart rate induced by the tachykinin NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10). Only LY303241 attenuated the decreases in mean arterial pressure and heart rate evoked by the tachykinin NK3 receptor agonist senktide. LY303870 and LY306740 appear to be the most interesting antagonists since they act in a specific and selective manner at the tachykinin NK1 receptor. The difference in the order of potency of the three antagonists to inhibit the hypotension and salivation elicited by substance P could be ascribed to their pharmacodynamic features or to the existence of different signal transduction mechanisms or receptor subtypes.

Anesthesia↗
PubMed1999

Pyrazolopyridine derivatives act as competitive antagonists of brain adenosine A1 receptors: [35S]GTPgammaS binding studies.

The effects of adenosine receptor ligands and three novel pyrazolopyridine derivatives on guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding to rat cerebral cortical membranes were examined. [35S]GTPgammaS binding was stimulated in a concentration dependent manner by several adenosine receptor agonists. The adenosine A2a receptor selective agonist, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), was ineffective confirming specificity for adenosine A1 receptor activation. 2-Chloro-N6-cyclopentyladenosine (CCPA; 10(-7) M)-stimulated [35S]GTPgammaS binding was inhibited by xanthine and pyrazolopyridine based adenosine receptor antagonists. The concentration-response curve for CCPA-stimulated [35S]GTPgammaS binding was shifted to the right with increasing concentrations of antagonist without significant changes in maximal response. Schild analyses determined pK(B) values of 8.97, 8.88, 8.21, 8.16, 7.79 and 7.65 for 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), 6-oxo-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl)-1(6H)-pyridazinebutyric+ ++ acid (FK838), 9-chloro-2-(2-furyl)[1,2,4]triazolo-[1,5c]quinazolin-5-amine (CGS 15943), 8-cyclopentyl-1,3-methylxanthine (CPT) and (R)-1-[(E)-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352), respectively. Schild slopes were close to unity, confirming that these novel pyrazolopyridine derivatives act as competitive antagonists at rat brain adenosine A1 receptors.

Adenosine↗
PubMed1977

Profiles of prostaglandins A, B, E and F (series I and II) obtained by gas chromatography with multiple-ion detection.

A new method is presented for the simultaneous one-step derivatization of prostaglandins A1, A2, B1, B2, E1, E2, F1alpha and F2alpha with N,O-bis(trimethylsilyl)trifluoroacetamide-piperidine. The procedure provides stable and reproducible trimethylsilyl derivatives that show good chromatographic properties on OV-17 and OV-225 columns, and precludes any significant degree of interconversion of the prostaglandins. The prostaglandins F, B and E are determined as the corresponding tetrakis(trimethylsilyl), bis(trimethylsilyl) and 9-enol-tetrakis(trimethylsilyl) derivatives, respectively. The enolization of prostaglandins E proceeds quantitatively only if piperidine is added to the acetamide. This mixture also produces the novel derivative 9-piperidyl-tris(trimethylsilyl)prostaglandin A. Evidence is also presented on the quantitative injection losses due to the type of syringe used (1micronl or 10 micronl). A modified extraction procedure has been applied to samples of human seminal fluid. The procedure, which involves the centrifugation of the samples, allows the recovery of all of the prostaglandins in one fraction, which is then derivatized and screened by combined gas-liquid chromatography-multiple-ion detection techniques in order to identify the individual compounds.

Chromatography, Gas↗
PubMed2000

Peroxynitrite-induced DNA damage in the supF gene: correlation with the mutational spectrum.

Tissue inflammation and chronic infection lead to the overproduction of nitric oxide and superoxide. These two species rapidly combine to yield peroxynitrite (ONOO(-)), a powerful oxidizing and nitrating agent that is thought be involved in both cell death and an increased cancer risk observed for inflamed tissues. ONOO(-) has been shown to induce single-strand breaks and base damage in DNA and is mutagenic in the supF gene, inducing primarily G to T transversions clustered at the 5' end of the gene. The mutagenicity of ONOO(-) is believed to result from chemical modifications at guanine nucleobases leading to miscoding DNA lesions. In the present work, we applied a combination of molecular and analytical techniques in an attempt to identify biologically important DNA modifications induced by ONOO(-). pUC19 plasmid treated with ONOO(-) contained single-strand breaks resulting from direct sugar damage at the DNA backbone, as well as abasic sites and nucleobase modifications repaired by Fpg glycosylase. The presence of carbon dioxide in the reaction mixture shifted the ONOO(-) reactivity towards reactions at nucleobases, while suppressing the oxidation of deoxyribose. To further study the chemistry of the ONOO(-) interactions with DNA, synthetic oligonucleotides representing the mutation-prone region of the supF gene were treated with ONOO(-), and the products were analyzed by liquid chromatography-negative ion electrospray ionization mass spectrometry (LC-ESI(-) MS) and tandem mass spectrometry. 8-Nitroguanine (8-nitro-G) was formed in ONOO(-)-treated oligonucleotides in a dose-dependent manner with a maximum at a ratio of [ONOO(-)]: [DNA]=10 and a decline at higher ONOO(-) concentrations, suggesting further reactions of 8-nitro-G with ONOO(-). 8-Nitro-G was spontaneously released from oligonucleotides (t(1/2)=1 h at 37 degrees C) and, when present in DNA, was not recognized by Fpg glycosylase. To obtain more detailed information on ONOO(-)-induced DNA damage, a restriction fragment from the pSP189 plasmid containing the supF gene (135 base pairs) was [32P]-end-labeled and treated with ONOO(-). PAGE analysis of the products revealed sequence-specific lesions at guanine nucleobases, including the sites of mutational "hotspots." These lesions were repaired by Fpg glycosylase and cleaved by hot piperidine treatment, but they were resistant to depurination at 90 degrees C. Since 8-nitro-G is subject to spontaneous depurination, and 8-oxo-guanine is not efficiently cleaved by piperidine, these results suggest that alternative DNA lesion(s) contribute to ONOO(-) mutagenicity. Further investigation of the identities of DNA modifications responsible for the adverse biological effects of ONOO(-) is underway in our laboratory.

Base Sequence↗
PubMed1997

Synthesis of some Mannich bases of 1-cyclohexylidene-N(1,2-dihydro-2-oxo-3H-indol-3-ylidene) thiosemicarbazones and their antibacterial activity.

Some Mannich bases of 1-cyclohexylidene-N(1,2-dihydro-2-oxo-3H-indol-3- ylidene) thiosemicarbazones have been prepared by employing formaldehyde and morpholine and piperidine as secondary amines. These Mannich bases have been characterised on the basis of different physico chemical evidences. Like some alkaloids, they also form reineckate complexes which serve for their estimation. Antibacterial activity of the synthesised Mannich bases has been studied by employing nine bacterial strains. Chloro group at position 5 broadened the spectrum of activity. Compounds with piperidine showed better activity than the compounds with morpholine, against almost all the organisms used (except 1 or 2 occasions).

Anti-Infective Agents↗
PubMed2001

Polar nitrogen compounds and their behaviour in the drinking water treatment process.

Aliphatic and alicyclic amines as well as ethanolamines are extremely polar compounds, frequently found in the environment, and some of them have high toxicity. To address the contamination of selected German surface waters examined and the importance of bank filtration in Eastern Germany, investigations on the behaviour of polar organic nitrogen compounds during water treatment were carried out. Test conditions were designed appropriately for drinking water treatment conditions, and the tests were carried out using model water as well as bank filtrate. Test filter studies of microbial degradation of selected compounds demonstrated the following order of biodegradability: ethanolamine > dimethylamine > pyrrolidine > ethylenediamine. piperidine > diethylamine > morpholine > piperazine > cyclohexylamine. Flocculation tests using iron salts as well as aluminium salts as coagulants showed very low removal rates for the amines. The best results for the removal of the polar organic nitrogen compounds from the water were obtained using ozonation. Based on the reaction-rate constants, the order of degradation by ozone is: piperazine > morpholine > ethylenediamine > piperidine, cyclohexylamine > dimethylamine > ethanolamine > pyrrolidine > diethylamine. Disinfection by chlorine-containing agents under drinking water treatment conditions did not give effective elimination of the selected polar nitrogen compounds.

Amines↗
PubMed2003

Molecular markers of anthropogenic activity in sediments of the Havel and Spree Rivers (Germany).

Detailed gas chromatographic/mass spectrometric analyses have been applied to sediment samples of the Havel and Spree River, tributaries to the Elbe River, in order to identify specific molecular markers of anthropogenic activities. Despite a wide variety of lipophilic organic compounds from diffuse anthropogenic contamination, a local emission of an industrial point source was reflected by specific markers including halogenated compounds and nitrogen containing substances (4-ethylnitrobenzene, formyl piperidine, acetyl piperidine). In addition to well-known anthropogenic markers various new molecular tracers were detected and are discussed, namely plasticizers (alkylsulfonic acid aryl esters, tributyl and tricresyl phosphates), synthetic fragrances (galaxolide, tonalide, 4-oxoisophorone), additives of personal care products (4-methoxycinnamic acid 2-ethylhexyl ester, benzyl benzoate, dibenzyl ether, benzophenone), occurring due to sewage treatment plant input.

Cosmetics↗
PubMed2003

Synthesis of the major metabolites of paroxetine.

Paroxetine is a well-known antidepressant, used worldwide in therapeutics. In comparison with other selective serotonin reuptake inhibitors, it exhibits the highest activity in serotonin reuptake inhibition. Paroxetine metabolism initially involves its demethylenation to the catechol intermediate, which is then O-methylated at positions C3 or C4. Herein, the chemistry resulting in the syntheses of these metabolites (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine and (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine is described starting from the common intermediate (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. Additionally, the common intermediate was used to synthesize paroxetine, which had the same structure and stereochemistry as commercial paroxetine, thereby confirming our synthetic route.

Animals↗
PubMed2001

Novel monoamine transporter ligands reduce cocaine-induced enhancement of brain stimulation reward.

Six novel monoamine reuptake inhibitors were screened for their intrinsic effects on brain stimulation reward (BSR), as well as for their potential to reduce cocaine-induced reward-enhancement in that paradigm. Two of the compounds, nocaine-3B and 5-ara-74A (disubstituted piperidines) significantly reduced locus of rise (LOR), threshold measure of reward, at some doses. One compound, 1-RV-96A (a hybrid of the GBR and WIN-like agents) significantly reduced reward (increased LOR), but only at the highest dose tested. No effect of dose was found for MC9-20 (a GBR-like acyclic analogue of the N-bisarylmethoxyethyl-N'-phenylpropyl piperazine), nocaine-250B or 4-ara-42C (disubstituted piperidines). When cocaine (10 mg/kg, ip) and selected, hedonically neutral doses of novel compounds were combined, the following findings were obtained: MC9-20 (2.5 mg/kg, ip) showed a significant increase in cocaine-induced reward enhancement (0.2 log units or 53%). In contrast, nocaine-250B and 1-RV-96A (both at 10 mg/kg, ip) demonstrated a significant reduction (0.13 log units or 41%) in cocaine-induced reward enhancement (P<.01 and P<.05, respectively), as measured by changes in LOR. There were no differences in the maximum behavioral output (MAX) at either dose of each of the six drugs, or when selected doses were combined with cocaine. These results indicate that nocaine-250B and 1-RV-96A constitute two potential anticocaine compounds worthy of further behavioral and biochemical evaluation.

Animals↗
PubMed2002

Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)(1B) receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT(1B) receptors and has been employed for characterization of cerebral 5-HT(1B) receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT(1B) sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t(1/2)=3.4 min), >90% specific binding and high affinity (K(d)=0.6 nM) for a homogeneous population of receptors with a density (B(max)) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT(1B) agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pK(i), 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (minus sign)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291; <5.0). Similarly, affinities were established for 13 chemically diverse antagonists, including N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125,743; pK(i), 9.1), (-)cyanopindolol (9.0), (-)-tertatolol (8.2), N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl)biphenyl-4-carboxamide (GR127,935; 8.2), N-[3-(1,4-benzodioxan-5-yl)piperidin-4-yl]N-(indan-2yl)amine (S18127; 7.9), metergoline (7.8), (-)-pindolol (7.6), 1'-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] (SB224,289; 7.5) and ketanserin (<5.0). These rank orders of affinity correspond to the binding profile of 5-HT(1B) rather than 5-HT(1D) receptors. The low affinities of L775,066 and PNU109,291 versus L694,247 should be noted, as well as the low affinity of ketanserin as compared to SB224,289. Finally, in line with species differences, the affinities of several ligands including CP93,129, RU24,969, (-)-pindolol and (-)-propanolol in rat 5-HT(1B) sites were markedly different to guinea pig 5-HT(1B) sites labelled with [3H]GR125,743. In conclusion, [3H]GR125,743 is an appropriate tool for the radiolabelling of native, rat 5-HT(1B) receptors and permitted determination of the affinities of an extensive series of ligands at these sites.

Animals↗
PubMed2000

The low affinity PCP sites in the rat cerebellum not only bind TCP-like but also BTCP-like structures.

Congeners of the potent dopamine (DA) re-uptake inhibitor 1-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) are unexpectedly able to bind in the rat cerebellum, although this structure is devoid of dopaminergic nerve endings. In line with previous studies the hypothesis that they bind to low affinity PCP sites labelled with [3H]TCP in the rat cerebellum, even though they do not bind to the high affinity PCP sites in the forebrain, was considered. Analogues of 1-[1-(2-thiophenyl)cyclohexyl]piperidine (TCP) and BTCP with a modified aromatic moiety and with O or S atoms substituted in the cyclohexyl ring were prepared and tested in competition experiments both in rat forebrain and cerebellum membranes labelled with [3H]TCP, and in rat striatum membranes labelled with [3H]BTCP. Results indicated that BTCP and congeners could bind to low affinity PCP sites labelled with [3H]TCP in the rat cerebellum with a decrease of the selectivity for the DA transporter. On the contrary, some TCP analogues displayed a very high selectivity for these low affinity sites; they might be important pharmacological tools to elucidate the nature and function at yet unknown of these sites.

Animals↗
PubMed2000

Synthesis and activity of 3-pyridylamine ligands at central nicotinic receptors.

A series of thirty 2-(3-pyridylaminomethyl)azetidine, pyrrolidine and piperidine analogues as nicotinic acetylcholine receptor (nAChR) ligands was explored. In general, pyrrolidinyl and many azetidinyl compounds were found to bind with enhanced affinity relative to the piperidines. In the three series, the parallel structural changes (stereochemistry, N-methylation and/or chloro substitution) do not consistently lead to parallel shifts in affinity. The more active compounds (K(i) affinity values ranging from 8.9 to 90 nM) were about as analgesic as nicotine in a tail-flick assay in mice after subcutaneous injections.

Amines↗
PubMed2003

Conformationally constrained butyrophenones as new pharmacological tools to study 5-HT 2A and 5-HT 2C receptor behaviours.

This study presents new pharmacological and molecular modelling studies on a recently described series of conformationally constrained butyrophenones. Alignment-free three-dimensional quantitative structure-activity relationship models developed on the basis of GRid Independent descriptors and partial least squares regression analysis, allow feasible predictions of activity of new compounds and reveal structural requirements for optimal affinity, particularly in the case of the 5-HT(2A) receptor. The requirements for the 5-HT(2A) affinity consist in a precise distance between hydrogen bond donor (protonated amino group) and hydrogen bond acceptor groups, as well as an optimal distance between the protonated amino group and the farthest extreme of the compounds. Another significant result has been the characterisation of two structurally similar compounds as interesting pharmacological tools (1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine and 1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine). In spite of their structural similarity, the first compound shows clearly higher affinity for the 5-HT(2C) receptor (about 100 fold) and higher Meltzer ratio (1.17 vs. 0.99) than the second. Moreover, the first compound inhibits arachidonic acid release in a biphasic concentration-dependent way in functional experiments at the 5-HT(2A) receptor and it acts as inverse agonist at the 5-HT(2C) receptor, behaviours that are not shown by the second compound.

Animals↗
PubMed2001

Distinct muscarinic receptors enhance spontaneous GABA release and inhibit electrically evoked GABAergic synaptic transmission in the chick lateral spiriform nucleus.

The effects of muscarinic agonists on GABAergic synaptic transmission were examined using whole-cell patch-clamp recording in chick brain slices containing the lateral spiriform nucleus. Bath application of muscarine (10 microM) both increased the frequency of spontaneous GABAergic postsynaptic currents and reduced the amplitude of evoked GABAergic polysynaptic postsynaptic currents elicited by focal afferent fiber electrical stimulation. Both of these muscarinic actions were reversible and dose-dependent. Two M(1) antagonists, telenzepine and pirenzipine, and to a lesser extent the M(2) antagonist methoctramine, protected against muscarine's inhibition of the evoked polysynaptic currents. Other M(2) antagonists (tripitramine and gallamine) as well as the M(3) antagonist 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride) and an M(4) antagonist (tropicamide) provided little or no protection against muscarine in this assay. In contrast, 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride, tropicamide and telenzepine, but not pirenzepine, methoctramine, tripitramine and gallamine, blocked muscarine's enhancement of spontaneous GABAergic currents. McN-A-343 [(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride] and CDD-0097 (5-propargyloxycarbonyl-1,4,5,6-tetrahydropyrimidine hydrochloride), two M(1) agonists, mimicked muscarine's inhibition of the evoked polysynaptic GABAergic currents but did not mimic muscarine's enhancement of spontaneous GABAergic currents. Both actions of muscarine persisted when slices were pretreated with pertussis toxin or N-ethylmaleimide, which inactivate G-proteins coupled to M(2) and M(4) receptors while leaving G-proteins coupled to M(1), M(3) and M(5) receptors intact. Muscarine had no significant effect on the amplitude of the direct postsynaptic current elicited by exogenous GABA in the presence of tetrodotoxin. The results demonstrate that distinct muscarinic receptors oppositely modulate GABAergic transmission in the lateral spiriform nucleus. The receptor mediating the inhibition of evoked GABAergic polysynaptic currents is pharmacologically similar to an M(1) receptor, while the enhancement of spontaneous GABAergic currents appears to be mediated by an M(3) receptor.

Animals↗
PubMed1998

Intrastriatal glial cell line-derived neurotrophic factor promotes sprouting of spared nigrostriatal dopaminergic afferents and induces recovery of function in a rat model of Parkinson's disease.

The ability of intrastriatally-administered glial cell line-derived neurotrophic factor to induce reinnervation and functional recovery in the partially-lesioned nigrostriatal dopamine system was explored in rats subjected to an axon terminal lesion induced by injection of 6-hydroxydopamine into the striatum. Glial cell line-derived neurotrophic factor was administered as multiple intrastriatal injections (10 x 5 micrograms) over a three-week period starting four weeks after the 6-hydroxydopamine injection, i.e. at the time when the acute phase of degeneration of the nigral dopamine neurons is complete. In the control group the lesion induced a 75-90% reduction of the dopaminergic innervation in the dorsolateral striatum (assessed by [3H]N-[1-(2-benzo(b)thiopenyl)cyclohexyl]piperidine-labelled dopamine uptake sites), and an approximately 50% reduction in the number of tyrosine hydroxylase-positive cell bodies in the central part of the substantia nigra, accompanied by a significant impairment in spontaneous motor behaviour, as assessed by a forelimb stepping test. In the glial cell line-derived neurotrophic factor-treated animals striatal [3H]N-[1-(2-benzo(b)thiopenyl)cyclohexyl]piperidine binding was restored to 70-95% of normal and contralateral forelimb stepping was completely normalized. The extent of striatal denervation in the individual lesioned and treated animals was well correlated with the performance of the affected limb in the stepping test. These results show that intrastriatal glial cell line-derived neurotrophic factor can stimulate substantial axonal sprouting and reinnervation of the partially deafferated striatum to a degree sufficient to reverse the lesion-induced deficit in spontaneous motoric behaviour, indicating that a direct action of glial cell line-derived neurotrophic factor on spared dopaminergic afferents in the striatum may be important for functional recovery in the rat Parkinson model.

Animals↗