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PubMed2003

Methyridine (2-[2-methoxyethyl]-pyridine]) and levamisole activate different ACh receptor subtypes in nematode parasites: a new lead for levamisole-resistance.

1. The development of resistance to all chemotherapeutic agents increases and needs to be addressed. We are interested in resistance in parasitic nematodes to the anthelmintic levamisole. During studies on methyridine, we found that it gave us a new insight into pharmacological changes associated with levamisole resistance. Initially, electrophysiological investigation using a two-micropipette current-clamp recording technique revealed that methyridine acts as a cholinergic agonist on nematode muscle receptors (Ascaris suum). Methyridine (>30 microm) produced reversible concentration-dependent depolarizations and increases in input conductance. Mecamylamine (30 microm) and paraherquamide (0.3 microm) produced reversible antagonism of the depolarization and conductance responses to methyridine. These observations suggest that methyridine, like acetylcholine and levamisole, gates ion channels on the muscle of parasitic nematodes. 2. The antagonistic effects of dihydro-beta-erythroidine and paraherquamide on methyridine-induced contractions of A. suum muscle flaps were then examined to determine if methyridine showed subtype selectivity for N-subtype (nicotine-sensitive) or L-subtype (levamisole-sensitive) acetylcholine receptors. Dihydro-beta-erythroidine weakly antagonized the effects of methyridine (but had no effect on levamisole responses). The antagonism of methyridine (pA2, 5.9) and nicotine (pA2, 6.1) by paraherquamide was similar, but was less than the antagonism of levamisole (pA2, 7.0). The antagonist profiles suggested that methyridine has a selective action on the N-subtype rather than on the L-subtype. 3. A novel use for a larval inhibition migration assay was made using L3 larvae of Oesophagostomum dentatum. Inhibitory effects of nicotine, levamisole, pyrantel and methyridine on the migration of larvae of levamisole-sensitive (SENS) and levamisole-resistant (LEV-R) isolates were tested at different concentrations. Levamisole and pyrantel (putative L-subtype-selective agonists) concentration-response plots were displaced to the right in LEV-R isolates. Nicotine (an N-subtype-selective agonist) and methyridine produced little shift in concentration-response plots in the LEV-R isolates. Resistance dose ratios were used to calculate the relative selectivity, rhoL, for the L-type receptor (levamisole rhoL=1.0; pyrantel rhoL=0.93; methyridine rhoL=0.17; nicotine rhoL=0.06). These observations reveal an N-subtype-selective action of methyridine and suggest that levamisole resistance may be associated with a loss of the L-subtype, but not the N-subtype receptors. The pharmacology of methyridine suggests an approach for the treatment of levamisole-resistant parasites.

Animals↗
PubMed2000

Evidence that nicotinic alpha(7) receptors are not involved in the hyperlocomotor and rewarding effects of nicotine.

Neuronal nicotinic receptors are comprised of combinations of alpha(2-9) and beta(2-4) subunits arranged to form a pentameric receptor. Currently, the principal central nervous system (CNS) subtypes are believed to be alpha(4)beta(2) and a homomeric alpha(7) receptor, although other combinations almost certainly exist. The identity of the nicotinic receptor subtype(s) involved in the rewarding effects of nicotine are unknown. In the present study, using some recently described subtype selective nicotinic agonists and antagonists, we investigated the role of the alpha(7) nicotinic receptor in the mediation of nicotine-induced hyperactivity and self-administration in rats. The alpha(7) receptor agonists AR-R 17779 and DMAC failed to stimulate locomotor activity in both nicotine-nontolerant and -sensitized rats. In contrast, nicotine and the putative alpha(4)beta(2) subtype selective agonist SIB1765F increased activity in both experimental conditions. In nicotine-sensitized rats, the high affinity (including the alpha(4)beta(2) subtype) nicotinic antagonist dihydro-beta-erythroidine (DHbetaE), but not the selective alpha(7) antagonist methyllycaconitine (MLA), antagonized a nicotine-induced hyperactivity. Similarly, DHbetaE, but not MLA, pretreatment reduced nicotine self-administration. Electrophysiology experiments using Xenopus oocytes expressing the human alpha(7) receptor confirmed AR-R 17779 and DMAC to be potent agonists at this site, and further studies demonstrated the ability of systemically administered AR-R 17779 to penetrate into the CNS. Taken together, these results indicate a negligible role of alpha(7) receptors in nicotine-induced hyperlocomotion and reward in the rat, and support the view for an involvement of a member from the high-affinity nicotinic receptor subclass, possibly alpha(4)beta(2). Issues such as drug potency, CNS penetration, and desensitization of the alpha(7) receptor are discussed.

Animals↗
PubMedDate not supplied

Multiresidue method for determination of algal toxins in shellfish: single-laboratory validation and interlaboratory study.

A method that uses liquid chromatography with tandem mass spectrometry (LC/MS/MS) has been developed for the highly sensitive and specific determination of amnesic shellfish poisoning toxins, diarrhetic shellfish poisoning toxins, and other lipophilic algal toxins and metabolites in shellfish. The method was subjected to a full single-laboratory validation and a limited interlaboratory study. Tissue homogenates are blended with methanol-water (9 + 1), and the centrifuged extract is cleaned up with a hexane wash. LC/MS/MS (triple quadrupole) is used for quantitative analysis with reversed-phase gradient elution (acidic buffer), electrospray ionization (positive and negative ion switching), and multiple-reaction monitoring. Ester forms of dinophysis toxins are detected as the parent toxins after hydrolysis of the methanolic extract. The method is quantitative for 6 key toxins when reference standards are available: azaspiracid-1 (AZA1), domoic acid (DA), gymnodimine (GYM), okadaic acid (OA), pectenotoxin-2 (PTX2), and yessotoxin (YTX). Relative response factors are used to estimate the concentrations of other toxins: azaspiracid-2 and -3 (AZA2 and AZA3), dinophysis toxin-1 and -2 (DTX1 and DTX2), other pectenotoxins (PTX1, PTX6, and PTX11), pectenotoxin secoacid metabolites (PTX2-SA and PTX11-SA) and their 7-epimers, spirolides, and homoYTX and YTX metabolites (45-OHYTX and carboxyYTX). Validation data have been gathered for Greenshell mussel, Pacific oyster, cockle, and scallop roe via fortification and natural contamination. For the 6 key toxins at fortification levels of 0.05-0.20 mg/kg, recoveries were 71-99% and single laboratory reproducibilities, relative standard deviations (RSDs), were 10-24%. Limits of detection were <0.02 mg/kg. Extractability data were also obtained for several toxins by using successive extractions of naturally contaminated mussel samples. A preliminary interlaboratory study was conducted with a set of toxin standards and 4 mussel extracts. The data sets from 8 laboratories for the 6 key toxins plus DTX1 and DTX2 gave within-laboratories repeatability (RSD(R)) of 8-12%, except for PTX-2. Between-laboratories reproducibility (RSDR) values were compared with the Horwitz criterion and ranged from good to adequate for 7 key toxins (HorRat values of 0.8-2.0).

Animals↗
PubMed1984

An evaluation of fluorometric proteinase assays which employ fluorescamine.

The sensitivity and utility of proteinase assays employing fluorescamine, a compound which reacts with primary amines to form a fluorescent adduct, was assessed. As little as 1 ng of purified trypsin or clostridiopeptidase A could be detected within 3 h of incubation at 37 degrees C, using casein or gelatin as substrates. Increasing the incubation period to 18 h permitted the detection of 250 pg of each enzyme. When gelled collagen was utilized as substrate, the sensitivity to clostridiopeptidase A was reduced to 2.5 ng at 3 h and 500 pg at 18 h. The techniques could be used to measure the gelatinase, caseinase, and collagenase activities of culture media conditioned by synovial tissue. The main disadvantage of this assay is its susceptibility to interference by compounds which fluoresce or quench. This, in turn, necessitates additional blanks, which may render the assay tedious.

Animals↗
PubMed2004

Short synthesis of the 6,6-spiroketal cores of spirofungins A and B.

[reaction: see text] Initial efforts toward the total synthesis of the antifungal antibiotics spirofungins A and B are reported. A short and efficient synthesis of the C9-C20 6,6-spiroketal fragments of both compounds is described. This asymmetric approach uses a very efficient alkylation of a lithiated N,N-dimethylhydrazone followed by spiroketal formation under acidic conditions.

Alkylation↗
PubMed1997

Isolation and structure elucidation of 7,8-dideoxy-6-oxo-griseorhodin C produced by Actinoplanes ianthinogenes.

A novel product, isolated from a culture broth of Actinoplanes ianthinogenes fermented for producing purpuromycin, was purified and its structure established on the basis of physico-chemical data and chemical reactions. The new product resulted to be structurally related to griseorhodins, a group of hydroquinonic antibiotics obtained from Streptomyces californicus. This compound showed a weak activity against Gram-positive and resulted inactive against Gram-negative bacteria and Candida albicans.

Anti-Bacterial Agents↗
PubMed2003

Evaluation of the mutagenicity of antimalarial products isolated from Solanum nudum (Solanaceae).

Diosgenone is a major component of the hexane extract from the plant Solanum nudum (Solanaceae). The products from degraded and acetylated diosgenone that showed in vitro antimalarial activity against the FCB-2 strain of Plasmodium falciparum and methanol, dichloromethane and ethereal extracts of Solanum nudum were tested for their mutagenic activity using the Ames test with the TA-97a, TA-98, TA-100 and TA-102 strains of Salmonella typhimurium. These compounds were not mutagenic at the tested concentrations.

Acetylation↗
PubMed1993

[Studies on the diterpenoids on Teucrium quadrifarium Buch-Ham].

Six neo-clerodane diterpenoids were isolated from the acetone extract of Teucrium quadrifarium Buch-Ham (I, II, IV, V, VI and VII). Five of them (I, II, IV, V and VII) were identified as known compounds, teucvidin, 12-epi-teucvidin, teuflin, 19-acetyl-teuspinin and teucvidin, respectively. Compound VI was found to be a new neo-clerodane diterpene, named teuquadrin B. Its structure has been determined from the physical and spectral data.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Further characterization of the 5-HT1 receptors mediating cardiac sympatho-inhibition in pithed rats: pharmacological correlation with the 5-HT1B and 5-HT1D subtypes.

Serotonin (5-hydroxytryptamine; 5-HT) is capable of inhibiting the tachycardic responses elicited by sympathetic stimulation, but not by exogenous noradrenaline, in pithed rats pre-treated with desipramine. More recently, it has been shown that this cardiac sympatho-inhibitory response to 5-HT, mediated by prejunctional 5-HT1 receptors as well as putative 5-ht5A/5B receptors, is mimicked dose-dependently by the agonists CP 93,129 (r5-HT1B), sumatriptan (5-HT1B/1D) and PNU-142633 (5-HT1D). This study analysed further the pharmacological profile of the above 5-HT1 receptors. Continuous i.v. infusions of CP 93,129, sumatriptan or PNU-142633 (30 micro g kg(-1)min(-1) each) failed to modify the tachycardic responses to exogenous noradrenaline but inhibited those elicited by preganglionic (C7-T1) stimulation of the cardiac sympathetic outflow. These sympatho-inhibitory responses were unaltered after i.v. administration of physiological saline (1 ml kg(-1)) or the 5-HT1A receptor antagonist WAY 100635 (10 micro g kg(-1)). In contrast, the antagonist GR 127935 (5-HT1B/1D; 100 micro g kg(-1), i.v.) abolished the responses to CP 93,129, sumatriptan and PNU-142633, whilst SB224289 (5-HT1B; 300 micro g kg(-1), i.v.) abolished the responses to CP 93,129 without affecting those to sumatriptan and PNU-142633. Interestingly, BRL15572 (5-HT1D; 300 micro g kg(-1), i.v.) abolished the responses to PNU-142633 and attenuated those to sumatriptan, but not those to CP 93,129. WAY 100635, GR 127935, SB224289 and BRL15572, given alone at the above doses, failed to modify the sympathetically induced tachycardic responses. The 5-HT1 receptors producing cardiac sympatho-inhibition in pithed rats thus display the pharmacological profile of the 5-HT1B and 5-HT1D receptor subtypes.

Animals↗
PubMed1978

Formation of spirodilactone of 4-(2'-carboxyphenyl)-4,4-dihydroxybutyrate from 2-succinylbenzoate in cell-free extracts of Micrococcus luteus.

The enzyme mediated ATP- and, to a lesser extent, CoASH-dependent synthesis of the spirodilactone of 4-(2'-carboxyphenyl)-4,4-dihydroxybutyrate from 2-succinylbenzoate has been demonstrated in membrane-free extracts of Micrococcus luteus and Escherichia coli. The suggestion is made that the spirodilactone is the product of an aberrant reaction involving a compound that is normally an intermediate in the conversion of 2-succinylbenzoate to 1,4-dihydroxy-2-naphthoate.

Adenosine Triphosphate↗
PubMed1976

Derivatization of compounds at the origin of thin-layer plates with fluorescamine.

A method has been developed for the detection of compounds with primary amino groups on thin-layer chromatography (TLC) plates with fluorescamine. The compounds dissolved in buffer were applied to TLC plates and derivatized at the origin by developing with or dipping into an acetone-hexane solution of fluorescamine. Virtually all fluorescamine derivatives stayed at the origin, and they were subsequently separated using appropriate solvent systems. As little as 10 pmoles of fluorescamine-derivatized compound could be detected when viewed under a long-wave (366 nm) ultraviolet lamp. The method was applied to the analysis of peptides, amino acids and amines.

Amines↗
PubMed2005

Cyclization of lithiated pyridine and quinoline carboxamides: synthesis of partially saturated pyrrolopyridines and spirocyclic beta-lactams.

Lithiation of N-benzyl pyridine and quinoline carboxamides alpha to nitrogen gives anions that undergo intramolecular attack on the pyridine or quinoline ring, either directly or on activation of the ring by N-acylation. The resulting four-, five-, or six-membered-ring-containing compound may be oxidized, protonated, alkylated, or acylated to give a range of polycyclic heterocycles, including pyrrolopyridines, pyrroloquinolines, benzonaphthyridines, and azaspirocyclic beta-lactams. [reaction: see text]

Cyclization↗
PubMed1993

Attenuation of scopolamine-induced spatial memory deficits in the rat by cholinomimetic and non-cholinomimetic drugs using a novel task in the 12-arm radial maze.

The effects of cholinomimetic and non-cholinomimetic agents on spatial memory using a novel task in the 12-arm radial maze were investigated. The task was designed to reduce the tendency to use non-spatial strategies. Animals were repeatedly trained to retrieve food rewards from three arms, until a criterion level of performance was reached. Scopolamine (0.03 and 0.1 mg/kg SC), but not N-methylscopolamine (0.1 mg/kg SC) disrupted performance of this task. Physostigmine (0.3 mg/kg SC) and pilocarpine (30 mg/kg SC) completely reversed the deficit of performance produced by scopolamine. Furthermore, the ACE inhibitor Hoe 288 (10 nmol ICV) and the angiotensin AT1 receptor antagonist losartan (10 mg/kg SC) also significantly attenuated the scopolamine-induced deficit. These results show that this novel task in the radial maze is sensitive to the disruptive effects of scopolamine and can identify cognitive enhancing effects of both cholinomimetic and non-cholinomimetic drugs. Thus, this maze task provides a useful model for the evaluation of novel cognitive enhancing agents.

Angiotensin Receptor Antagonists↗
PubMed2001

[The effect of gabapentin and gabapentin-lactam on retinal ganglion cell survival. Situation after acute retinal ischemia in animal models].

BACKGROUND: Reduction in the excitatory and potentially toxic neurotransmitter glutamate can protect retinal ganglion cells. What are the effects of the antiepileptic drug gabapentin, for which antiglutamatergic effects have been described, and the new substance gabapentin-lactam (GBP-L) on retinal ganglion cell survival after retinal ischemia? METHODS: In 3 groups of 10 rats each, ischemia was induced by elevating the intraocular pressure of the left eye to 120 mmHg for 1 h. Saline, gabapentin (2 x 50 mg/kg intraperitoneally) and GBP-L (2 x 50 mg/kg intraperitoneally) were injected before and 5 h after ischemia. Two weeks later ischemic damage was quantified histologically by counting the number of neurons in the ganglion cell layer. In vitro transmitter release experiments were performed to obtain information on the effect of gabapentin and GBP-L on ischemia-induced glutamate release and the mechanism of action of GBP-L. RESULTS: In the control group 17% of the retinal ganglion cells survived ischemia. GBP-L doubled the number of the surviving cells while gabapentin was not effective in these experiments. In vitro gabapentin and GBP-L reduced ischemia-induced glutamate release by 35.7% and 42.5%, respectively. The blockade of ATP-sensitive potassium channels antagonized the effect of GBP-L completely. CONCLUSION: GBP-L is neuroprotective in retinal ischemia and diminishes the release of the excitatory neurotoxic amino acid glutamate. The effect of GBP-L might be mediated by ATP-sensitive potassium channels. Also gabapentin reduced glutamate release but was not neuroprotective in vivo.

Acetates↗
PubMed2004

Retinal ganglion cell survival is enhanced by gabapentin-lactam in vitro: evidence for involvement of mitochondrial KATP channels.

BACKGROUND: Recently, gabapentin-lactam (GBP-L) was shown to be neuroprotective in vivo. It has been suggested that GBP-L may act by opening mitochondrial ATP-sensitive potassium (K(ATP)) channels. We tested this hypothesis by quantifying the effect of GBP-L on the survival of purified retinal ganglion cells (RGCs). METHODS: RGCs were purified from early postnatal rat retinae by immunopanning with antibodies against Thy1.1 and cultured in serum-free medium for 2 days. Cell survival was quantified by counting vital cells under phase-contrast optics. Results were normalized to controls. RGCs were treated with various concentrations (3.2-320 microM) of GBP-L with and without 1 microM glibenclamide, blocking both plasmalemmal and mitochondrial K(ATP) channels, or 100 microM 5-hydroxydecanoate (5-HD), antagonizing selectively mitochondrial K(ATP) channels. For comparison, additional cultures were treated with 32 microM gabapentin, the parent drug of GBP-L. A combination of the neurotrophic factors BDNF and CNTF (50 ng/ml each) served as a positive control. RESULTS. GBP-L increased RGC survival to a maximum of 145+/-5% (mean +/- SEM) in a concentration-dependent manner. The pEC(50) was 5.0, CI95 [4.7, 5.3]. Preincubation with glibenclamide changed the dose-response of GBP-L, indicating that it acted as a competitive antagonist with a pA2 value of 6.8, CI95 [5.9, 7.5]. 5-HD completely blocked the survival-promoting effect of GBP-L. Gabapentin had no effect, whereas the combination of CNTF and BDNF enhanced survival to 177+/-9%. CONCLUSIONS: GBP-L, but not gabapentin, can promote the survival of cultured central nervous system neurons, possibly by opening mitochondrial K(ATP) channels. These results suggest further testing of GBP-L as a potentially neuroprotective drug.

Adenosine Triphosphate↗
PubMed2000

Behavioral effects of AMI-193, a 5-HT(2A)- and dopamine D(2)-receptor antagonist, in the squirrel monkey.

8-[3-(4-Fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4, 5]decan-4-one (AMI-193) was developed as a 5-HT(2A)-selective antagonist with in vivo activity suitable for behavioral studies. However, AMI-193 is a potent dopamine D(2)-receptor antagonist with low nanomolar affinity. Accordingly, D(2)-actions may contribute to its behavioral pharmacology. In the present study, the effects of AMI-193 on operant behavior were characterized in squirrel monkeys. In subjects trained under a fixed-interval (FI) schedule of stimulus termination, AMI-193 (0.003-0.01 mg/kg) dose-dependently decreased response rate. When administered in combination with cocaine (0.03-3. 0 mg/kg) or the selective dopamine uptake inhibitor, GBR 12909 (0. 03-3.0 mg/kg), the rate-decreasing effects of AMI-193 were reversed by both dopamine indirect agonists. In drug-discrimination experiments, AMI-193 (0.003 and 0.01 mg/kg) attenuated the discriminative-stimulus effects of cocaine. AMI-193 (0.003 and 0.01 mg/kg) also reduced response rate under a second-order schedule of i. v. self-administration of cocaine (0.1 mg/infusion). The profile of behavioral effects and drug interactions observed in the present study, in conjunction with the relatively high affinity of AMI-193 for dopamine D(2) receptors, suggests that its D(2)-antagonist effects play a prominent role in the behavioral pharmacology of AMI-193.

Animals↗