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At least 307 records · Page 17Linked to original sources
PubMed2002

Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure.

The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) is involved in many drug-related behaviors, including ethanol self-administration. In particular, VTA activity regulating ethanol consummatory behavior appears to be modulated through GABA(A) receptors. Previous exposure to ethanol enhances ethanol self-administration, but the mechanisms underlying this phenomenon are not well understood. In this study, we examined changes occurring at GABA synapses onto VTA DA neurons after a single in vivo exposure to ethanol. We observed that evoked GABA(A) IPSCs in DA neurons of ethanol-treated animals exhibited paired-pulse depression (PPD) compared with saline-treated animals, which exhibited paired-pulse facilitation (PPF). Furthermore, PPD was still present 1 week after the single exposure to ethanol. An increase in frequency of spontaneous miniature GABA(A) IPSCs (mIPSCs) was also observed in the ethanol-treated animals. Additionally, the GABA(B) receptor antagonist (3-aminopropyl)(diethoxymethyl) phosphinic acid shifted PPD to PPF, indicating that presynaptic GABA(B) receptor activation, likely attributable to GABA spillover, might play a role in mediating PPD in the ethanol-treated mice. The activation of adenylyl cyclase by forskolin increased the amplitude of GABA(A) IPSCs and the frequency of mIPSCs in the saline- but not in the ethanol-treated animals. Conversely, the protein kinase A (PKA) inhibitor N-[z-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide significantly decreased both the frequency of spontaneous mIPSCs and the amplitude of GABA(A) IPSCs in the ethanol-treated mice but not in the saline controls. The present results indicate that potentiation of GABAergic synapses, via a PKA-dependent mechanism, occurs in the VTA after a single in vivo exposure to ethanol, and such potentiation might be a key synaptic modification underlying increased ethanol intake.

Administration, Oral↗
PubMed1992

Purification and characterization of the mouse mammary tumor virus protease expressed in Escherichia coli.

The mouse mammary tumor virus (MMTV) protease gene was cloned into pGEX-2T, an Escherichia coli expression vector containing the glutathione S-transferase coding region of Schistosoma japonicum. The chimeric protein was formed by fusion of the glutathione S-transferase with a hexapeptide which contains a thrombin cleavage site, followed by the MMTV protease. Affinity chromatography on a glutathione-Sepharose 4B column was used to isolate the chimeric protein. After thrombin cleavage, the glutathione S-transferase and the protease were separated by gel filtration chromatography on a Sephadex G-75 column. The overall yield of the protease purification procedure was about 1 mg of protease/liter of culture, and the specific activity was 380 pmol/min.micrograms of enzyme. Like other retroviral proteases, the MMTV enzyme was active as a dimer, showed maximum activity at pH between 4 and 6, and could be inhibited by pepstatin A and a phosphinic acid derivative HIV-1 protease inhibitor. Enzymatic characterization of this protease reveals its broad specificity, showing a clear preference for the oligopeptide substrate mimicking the cleavage site at the amino-terminal end of the capsid protein (kcat/Km = 9725.5 M-1.s-1). The chimeric protein was also an active dimer and showed a similar Km (17 microM) for such an oligopeptide, although its kcat was about 10 times smaller. Autocatalytic processing of the MMTV protease was observed after expression of clones containing the natural cleavage site, as it occurs at the amino-terminal end of the viral protease, instead of the thrombin-sensitive sequence.

Amino Acid Sequence↗
PubMed1992

Functional evidence for multiple gamma-aminobutyric acidB receptor subtypes in the rat cerebral cortex.

The aim of this work was the identification of pharmacologically distinct subtypes of gamma-aminobutyric acidB (GABAB) receptors in the central nervous system. Inasmuch as GABAB receptors are often sited on axon terminals where they mediate inhibition of transmitter release, we chose as models the GABAB receptors mediating inhibition of release of 1) endogenous GABA; 2) endogenous glutamate; and 3) somatostatin-like immunoreactivity (SRIF-LI). The experimental set up consisted of rat cerebrocortical synaptosomes depolarized in superfusion with 12 or 15 mM KCl. Endogenous GABA and glutamate were measured by high-performance liquid chromatography and SRIF-LI by radioimmunoassay. The selective GABAB receptor agonist (-)-baclofen inhibited in a concentration-dependent manner the K(+)-evoked release of GABA, glutamate and SRIF-Ll with similar potencies and efficacies [EC50 values, 1.1-1.5 microM; maximal inhibition, 45-50% at about 10 microM (-)-baclofen]. The GABAB receptor antagonist phaclofen concentration-dependently reduced the effects of (-)-baclofen on the release of GABA and SRIF-Ll but not on the release of glutamate, where it was ineffective up to 1000 microM. The rank order of potency (Ki values are shown in parentheses) are: SRIF-Ll (7.8 microM); GABA (10.4 microM); and glutamate (greater than 115 microM). The novel GABAB receptor antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP 35348) displayed a different pattern on the three release systems examined (Ki values are shown in parentheses): SRIF-Ll (0.38 microM); glutamate (0.48 microM); and endogenous GABA (greater than 115 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Analysis of responses to St. John's Wort in the feline pulmonary vascular bed.

OBJECTIVE: To test the hypothesis that St. John's wort induces a depressor response in the feline pulmonary vascular bed and identify the pathways involved in the mediation or modulation of these effects. DESIGN: Prospective vehicle controlled study. SETTING: University research laboratory. SUBJECTS: Intact chest preparation; adult mongrel cats. INTERVENTIONS: In separate experiments, the effects of L-N5-(1-Iminoethyl) ornithine hydrochloride (L-NIO), a nitric oxide synthase inhibitor, glibenclamide, an ATP-sensitive K+ channel blocker, meclofenamate, a non-selective cyclo-oxygenase (COX) inhibitor, nicardipine, a calcium channel blocker, bicuculline, a GABAA receptor antagonist, and saclofen, a GABAB antagonist, were investigated on pulmonary arterial responses of St. John's wort (SJW), pinacidil, an ATP-sensitive K+ channel activator, bradykinin, an inducer of nitric oxide synthase, 3-aminopropyl (methyl) phosphinic acid, hydrochloride (SKF-97541), a GABAB receptor agonist and muscimol, a GABAA receptor agonist. MEASUREMENTS AND MAIN RESULTS: Lobar arterial perfusion pressure and systemic pressure were continuously monitored, electronically averaged and permanently recorded. Under elevated tone conditions in the isolated left lower lobe vascular bed of the cat, SJW induced a dose-dependent vasodepressor response that was not significantly altered after administration of L-NIO, glibenclamide, meclofenamate or saclofen. Responses to SJW were significantly reduced after administration of either nicardipine or bicuculline. When the calcium channel blocker nicardipine was administered in addition to the GABA blocker bicuculline, there was near complete attenuation of the SJW-induced vasodepressor responses. CONCLUSIONS: The results of the present study suggest that SJW has potent vasodepressor activity in the pulmonary vascular bed of the cat and that this response is mediated or modulated by both a calcium channel and GABA receptor sensitive pathway.

Acetylcholine↗
PubMed1991

[Use of a new M-cholinolytic drug KG-62 for correction of the course of experimental stomach ulcer].

The preparation KG-62 related to iodomethylates of hydroxyalkyl phosphinic acids with muscarinolytic effect has been studied. The study provides data on the development of experimental gastric ulcer among rats after injections of the preparation. On the basis of morphologic, morphometric and biochemical data it has been stated that the preparation KG-62 in a 5 mg/kg dose has a more strong effect leading to quick gastric ulcer healing. It was supposed that not only suppressing action on hydrochloric acid and pepsinogen secretion lies in the mechanism of the effect but also the activation of physiologic regulation in intact tissue.

Animals↗
PubMedDate not supplied

[Toxic and pharmacological characteristics of armin and nibufin homologs].

The experimental studies of alkylesters of phosphonic and phosphinic acids, close homologues of armine and nibufin, showed this series of compounds to have a strongly marked anticholinesterase action. All the substances produce an inhibitory effect on the central nervous system, raise the tone of the smooth muscles on an isolated strip of rabbit small intestine and induce a miotic pupil in the animals. Introduction of butyl radicals into molecules of phosphonic acid derivatives results in diminution of toxicity and a slight decrease in anticholinesterase activity. By their properties butyl paranitrophenyl esters of ethyl- and butylphosphonic acids are closely related to armine and nibufin.

Animals↗
PubMed1995

Multiple GABA receptor subtypes mediate inhibition of calcium influx at rat retinal bipolar cell terminals.

Inhibitory effects of GABA on K(+)-evoked Ca2+ influx into rat retinal bipolar cell terminals were studied using calcium imaging methods. Application of high K+ evokes a sustained, reversible increase in [Ca2+]i at bipolar cell terminals, which occurs mainly via dihydropyridine-sensitive (L-type) Ca2+ channels. There are at least two GABA receptor subtypes coexisting at bipolar cell terminals: a conventional GABAA receptor and a bicuculline/baclofen-insensitive GABA receptor. Activation of either GABA receptor inhibited the K(+)-evoked Ca2+ response. However, these two GABA receptor subtypes have distinct properties. GABAA receptors suppress the Ca2+ response only at relatively high concentrations of agonist, and with fas kinetics and a narrow dynamic range. In contrast, the bicuculline/baclofen-insensitive GABA receptors produce inhibition on the Ca2+ response at a much lower concentration of agonist, and with slow onset and a wider dynamic range. The pharmacologic profile of the bicuculline/baclofen-insensitive GABA receptor at bipolar cell terminals is most similar to the GABAC receptor reported by Feigenspan et al. (1993). Unlike the GABAC receptors described in other species, it is extremely insensitive to picrotoxin. Therefore, it may be appropriate to refer to this receptor as a picrotoxin-insensitive GABAc receptor. 3-Aminopropyl(methyl)phosphinic acid (3-APMPA) and 3-aminopropylphosphonic (3-APA), two phosphate analogs of GABA, selectively antagonize the picrotoxin-insensitive GABAc receptors but not the GABAA receptors in this system. These results imply a functional role for multiple GABA receptors in regulating synaptic transmission at bipolar cell terminals.

Animals↗
PubMed1997

Antinociceptive profile of 3-alpha-tropanyl 2-(4-Cl-phenoxy)butyrate (SM-21) [corrected]: a novel analgesic with a presynaptic cholinergic mechanism of action.

The antinociceptive effect of (+/-)-3-alpha-tropanyl 2-(4-Cl-phenoxy)butyrate [corrected] (SM-21) (10-40 mg kg(-1) s.c., 10-30 mg kg(-1) i.p., 20-60 mg kg(-1) p.o., 3-20 mg kg(-1) i.v. and 5-20 microg per mouse i.c.v.) was examined in rodents and guinea pigs by using the hot-plate, abdominal constriction, tail-flick and paw-pressure tests. The antinociception produced by (+/-)-SM-21 was prevented by atropine, pirenzepine and hemicholinium-3 but not by quinpirole, R-(alpha)-methylhistamine, [1-[2(methylsufonyl)amino]ethyl]-4-piperidinyl]methyl-5-floro++ +-2-methoxy-1H-indole-3-carboxylate hydrochloride, N6-cyclopentyladenosine, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide, naloxone, 3-aminopropyl-diethoxy-methyl-phosphinic acid or reserpine. On the basis of the above data, it can be postulated that (+/-)-SM-21 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. Affinity profiles of (+/-)-SM-21 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M1, guinea pig atrium for M2, guinea pig ileum for M3 and immature guinea pig uterus for putative M4) have shown a selectivity ratio M2/M1 of 4.6 that, although very low, might be responsible for the antinociception induced by (+/-)-SM-21 through an increase in ACh extracellular levels. In the antinociceptive dose range, (+/-)-SM-21 did not impair mouse performance evaluated by the rota-rod and hole-board tests.

Analgesics↗
PubMed1997

[Angiotensin-converting enzyme inhibitors: recent therapeutic aspect].

Angiotensin-converting enzyme (ACE) inhibitors now have an accepted place in the treatment of hypertension and congestive heart failure. With the discovery and development of captopril, several other ACE inhibitors have been synthesized and introduced for clinical use. All ACE inhibitors bind to zinc ions located in the active site of the ACE molecule. ACE inhibitors can be classified according to the ligand of the zinc ion of ACE, into 3 different structural types: (1) the first type such as captopril has a sulphhydryl moiety as the ligand; (2) the second type such as enalapril uses a carboxyl moiety as the ligand; (3) the third type such as fosinopril uses neither a sulphhydryl nor carboxyl group, but a phosphinic acid as the zinc binding moiety. ACE inhibitors can also be classified according to the excretion route of their active moiety, into 2 different excretion route types:(1) excreated mainly through the kidney such as captopril, enalaprilat, lisinopril, benazeprilat, imdaprilat, trandraprilat, etc.; (2) excreated both in the bile and urine such as fosinoprilat, temocaprilat, zofenoprilat etc. ACE inhibitors have clinically beneficial effects not only for patients with either hypertension or congestive heart failure, but also can be used to prevent the progression of renal dysfunction induced by hypertension and diabetes mellitus.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Antinociceptive and antiamnesic properties of the presynaptic cholinergic amplifier PG-9.

The antinociceptive effect of 3 alpha-tropyl 2-(p-bromophenyl)propionate [(+/-)-PG-9] (10-40 mg kg-1 s.c.; 30-60 mg kg-1 p.o.; 10-30 mg kg-1 i.v.; 10-30 micrograms/mouse i.c.v.) was examined in mice, rats and guinea pigs by use of the hot-plate, abdominal-constriction, tail-flick and paw-pressure tests. (+/-)-PG-9 antinociception peaked 15 min after injection and then slowly diminished. The antinociception produced by (+/-)-PG-9 was prevented by the unselective muscarinic antagonist atropine, the M1-selective antagonists pirenzepine and dicyclomine and the acetylcholine depletor hemicholinium-3, but not by the opioid antagonist naloxone, the gamma-aminobutyric acidB antagonist 3-aminopropyl-diethoxy-methyl-phosphinic acid, the H3 agonist R-(alpha)-methylhistamine, the D2 antagonist quinpirole, the 5-hydroxytryptamine4 antagonist 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester hydrochloride, the 5-hydroxytryptamin1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide and the polyamines depletor reserpine. Based on these data, it can be postulated that (+/-)-PG-9 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. (+/-)-PG-9 (10-40 mg kg-1 i.p.) was able to prevent amnesia induced by scopolamine (1 mg kg-1 i.p.) and dicyclomine (2 mg kg-1 i.p.) in the mouse passive-avoidance test. Affinity profiles of (+/-)-PG-9 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M1, guinea pig atrium for M2, guinea pig ileum for M3 and immature guinea pig uterus for putative M4), have shown an M4/M1 selectivity ratio of 10.2 that might be responsible for the antinociception and the anti-amnesic effect induced by (+/-)-PG-9 through an increase in acetylcholine extracellular levels. In the antinociceptive and antiamnesic dose range, (+/-)-PG-9 did not impair mouse performance evaluated by the rota-rod test and Animex apparatus.

Amnesia↗
PubMed1998

Two cases of glufosinate poisoning with late onset convulsions.

Glufosinate ammonium (GLA), the active ingredient in the non-selective herbicide BASTA (18.5% GLA), is a phosphinic acid analogue of glutamic acid. We report 2 cases of GLA poisoning with late onset convulsions and increased serum CK in spite of low blood concentrations of GLA after hemodialysis. A 69-y-old female was admitted to the emergency department after taking 500 ml of BASTA. On arrival she was conscious, and gut decontamination, hemodialysis and hemoperfusion were performed. However, 8 1/2 hours after ingestion, general convulsions occurred. Her serum OK increased to a peak of 24,900 IU/L on the third day of admission. An 87-y-old male was admitted to the emergency department 3 1/2 hours after taking 200 ml of BASTA and receiving gastric lavage at a local emergency room. On arrival he was conscious, and serial activated charcoal and hemodialysis was performed. Blood concentration of GLA after hemodialysis decreased from 1.56 micrograms/ml to 0.68 micrograms/ml. Thirty hours after admission he had general convulsions. GLA was not detected in the cerebrospinal fluid 6 h after the convulsions. His serum CK increased to a peak of 17,870 IU/L on the fifth day of admission.

Aged↗
PubMed1999

Fullerene Derivatives Bearing a Phosphite Ylide, Phosphonate, Phosphine Oxide, and Phosphonic Acid: Synthesis and Reactivities.

Treatment of phosphites (P(OR)(3)) and MeO(2)CCCCO(2)Me with C(60) affords the corresponding fullerene derivatives (1, R = Me; 2, R = Et; 3, R = n-Bu) consisting of a phosphite ylide group and a cyclopropane ring on the fullerene moiety in high yields. NMR data indicate that all phosphite ylides 1-3 exist as mixtures of E and Z isomers. Under similar reaction conditions, the reaction of phosphinite PPh(2)(OMe) and MeO(2)CCCCO(2)Me with C(60) gives ylide 4. Ylides 1-3 readily undergo hydrolysis with HBr to give corresponding phosphonates 5-7 in excellent yields, while ylide 4 reacts with hydrobromic acid to afford phosphine oxide 8. A mechanism is proposed to account for the formation of these phosphonate derivatives. Further treatment of phosphonate derivative 5 with trimethylsilyl iodide followed by water gave phosphonic acid derivative 9 in 83% yield.

Journal Article↗
PubMed1993

Hepato-biliary and renal excretion in mice of charged and neutral gadolinium complexes of cyclic tetra-aza-phosphinic and carboxylic acids.

Tissue distribution of 21 new 157/153Gd complexes was measured at 5 min and 24 hr after an intravenous injection into mice. A complex was judged to be stable in vivo when the percentage of 153Gd retained in the liver and skeleton at 24 hr was comparable with that of 153Gd(DOTA)-. Complexes varied in net charge and lipophilicity and 20 were phosphinic or carboxylic acid derivatives of tetra-aza-cyclo-dodecane. Three anionic, lipophilic complexes were cleared predominantly by the hepato-biliary pathway and were stable in vivo. The remaining 18 complexes were cleared mainly by the kidneys. Of these 18, 1 anionic, 8 neutral, and 3 cationic complexes were stable in vivo. These findings augur well for the future of hepato-biliary and general purpose Gd contrast enhancing agents for MRI.

Animals↗
PubMed1992

[A phosphine-substituted diphosphonic acid (HMPD) for improved scintigraphic detection of bone lesions].

Although the radiopharmaceuticals used for bone scintigraphy are of very high quality, the search for an "ideal" agent continues. To optimise the detectability of bone lesions, we analysed 244 different 99mTc-labeled phosphonates in animal experiments. In osteosarcoma-carrying rats 99mTc-labeled 1-Hydroxy-3-methyl-phosphinic-1, 1-propanediphosphonic acid (HMPD) was shown to produce the best lesion/normal bone ratio. 99mTc-MDP was used as reference. The ratio was found to be 1.28 for 99mTc-HMPD. The transferability of our results in animals to the situation in man was studied in 10 patients with bone metastases. There was for 99mTc-HMPD an improvement of the lesion/normal bone ratio by more than 60% but also an additional reduction of the soft tissue contrast by about 40%. 15% of the metastases were detected by scintigraphy using 99mTc-HMPD only and not with 99mTc-MDP. The new agent should make possible a better and earlier discrimination of bone lesions in the scintigram.

Aged↗
PubMed2006

Synthesis of phosphine containing amino acids: utilization of peptide synthesis in ligand design.

Combinatorial chemistry has recently burst on the scene as a valuable tool for the discovery of new drug candidates. The ability to synthesize hundreds of compounds for screening is a useful complement to rational drug design. There are many similarities between the design of new therapeutic agents and the development of new asymmetric ligands, the most important of which is the limitation of a rational design strategy. For this reason a program was begun that would allow the use of combinatorial technology in the development of new ligands for transition metal catalyzed asymmetric reactions. Because of the large number of catalytic reactions they are involved in the system was based around phosphine ligands. This paper reports the synthesis of phosphine derivatives of alanine, proline, and the aromatic amino acids tyrosine and hydroxyphenylglycine. Examples of the use of these amino acids in the synthesis of peptides possessing helical and beta-turn secondary structures are presented. Metal complexes of these peptide-based ligands are used in hydrogenation and alkylation reactions.

Amino Acids↗