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PubMedDate not supplied

Sedative action of some substituted benzylamides.

Substituted benzylamide derivatives of amino acylamide (compound A,B,C, & D) were found to be less potent local anaesthetics than lignocaine and procaine. However, the four compounds exhibited sedation without ptosis and reduced spontaneous locomotor activity better than methaqualone. Compound A alone antagonised methylamphetamine induced hypermotor activity. The test compounds potentiated hexobarbitone induced hypnosis. Three compounds antagonised calcium induced stoppage of isolated heart of frog. Except compound C all caused a transitory fall of blood pressure in dog which was not blocked either by atropine or propranolol. These compounds showed neuromuscular blockade and possessed slight analgesic activity but were devoid of anticonvulsant and tranquillizing activity. LD 50 values were calculated to be 164.1 +/- 23.0, 229.1 +/- 51.0, 181.6 +/- 28.18 and 416+/-38.2 mg/kg for compounds A,B,C & D respectively.

Amides↗
PubMed1950

Anesthesia.

Explore the source record for details and available documents.

Anesthesia↗
PubMed1976

Relationship between effects of procaine and Ca on spontaneous electrical and mechanical activities of the smooth muscle cells of the guinea pig urinary bladder.

The relationships between the effects of procaine and those of Ca on the spontaneous electrical and mechanical activities of smooth muscle cells of the guinea pig urinary bladder were studied using both microelectrode and sucrose gap methods. Procaine(1, 7, and 15mM) depolarized the membrane and increased spontaneous spike freqency. The maximum rates of rise and fall and the after-hyperpolarization of the spike decreased. Enhanced spontaneous rhythmic contractions accompanied these membrane activities (1 mM). The tone of the preparation (resting rension) increased transiently and decreased gradually (7-15mM). These procaine effects were suppressed by the application of excess Ca (7.5 mM). The increased electrotonic potential induced by 7mM procaine was reduced by the addition of 7.5 mM Ca. Reduction of Ca concentration (0.8 and 0 mM) IN Krebs solution containing procaine further depolarized the membrane and decreased the spike amplitude. In Ca-deficient solution, the enhanced rhythmic contractions induced by procaine were slightly reduced. Compound D600 (1-3mg/1), manganese ion (Mn) (1-3 mM), and cobalt ion (CO) (1-3 MM) inhibited the effects of procaine on spike discharges and mechanical responses. From these results it is concluded that procaine action is related to that of Ca which controls the membrane permeability, since procaine depolarizes the membrane by reducing K conductance. Furthermore, action potentials observed in the Krebs solution containing procaine are considered to be Ca spikes, which seem to play an important role in excitation-contraction coupling in the guinea pig urinary bladder smooth muscle.

Action Potentials↗
PubMed1990

A non-archimedean theory of interaction of chemical compounds with membranes.

The permeability of procaine across axon membranes and the effect of formaldehyde (FA), crotonic aldehyde (CA) and glutaraldehyde (GA) on the compound action potential of frog sciatic nerve was studied by utilizing a non-archimedean (NA) model of the relaxation process. Such models allow a characterization of biosystems exhibiting more than one time scale. Expansions using Laguerre polynomials have been obtained for relaxation functions. The new approach is tested by fitting the model to the experimental data of other authors, and then applying to extract molecular level information from macroscopic data.

Action Potentials↗
PubMedDate not supplied

Effect of the cisplatin-procaine complex DPR in combination with several anticancer agents on murine P388 leukemic cells in vitro and in vivo.

We evaluated in vitro the antiproliferative activity of DPR (Fig. 1), a new cisplatin-derived compound, in combination with five conventional anticancer drugs: the antimetabolites 5-fluorouracil (5FU) and methotrexate (MTX), the alkylating agent mitomycin C (MMC), the antimicrotubule agent taxol (TAX) and the intercalating agent of the antracycline group doxorubicin (DOX), against murine P388 leukemic cells. MTT assay was used to determine growth inhibition after incubation of cells for 72 hours in the presence of single or combined drugs. The additive, synergistic or antagonistic nature of the combined drug effect was determined using the isobole method. In our cellular model, synergism was the prevailing result observed when DPR was combined with MMC. Conversely, antagonism was observed when DPR was combined with TAX. When DPR was administered together with the other antineoplastic drugs, the final effect was dependent on the concentrations of single agents. The study in vitro of the association between DPR and MMC was extended in vivo in BDF-1 female mice bearing i.p. P388 leukemic cells. Our data in vivo confirmed those obtained in vitro, demonstrating the therapeutic advantage of the association of ineffective doses of DPR (2 and 7 mg/kg) and MMC (3.2 mg/kg) over the administration of MMC alone.

Animals↗
PubMed1994

Synthesis and pharmacochemistry of some new aminoketones with local anaesthetic activity.

The synthesis of some new 1-indane- and 1-(1',2',3',4'-tetrahydronaphthalene-1-spiro-3''-ryrrolidino-2'',5 ''- dione)-3-amino-substituted-butanones-2, having the structural characteristics for local anaesthetic activity, is reported. These aminoketones were synthesized using a modified Mannich reaction. The structure of the intermediate and final products were identified by elemental and spectroscopic analyses (IR, 1H-NMR, MS). The physicochemical parametres pKa and logP were determined experimentally, and they were also calculated using the appropriate Taft's equation and the Rekker's hydrophobic fragmental constants, respectively. The local anaesthetic activity of the synthesized compounds was determined in vitro on isolated frog's nerve, using an improved evoked action potential technique. The biological results were expressed as relative activities (RA) to procaine, used as reference compound. These RA of the investigated compounds were found to lie between 0.50-0.85. An attempt was made to correlate the local anaesthetic activity with the values of the investigated physicochemical parameters.

Action Potentials↗
PubMed1990

The effect of amino acids, monoamines and polyamines on pyruvate dehydrogenase activity in mitochondria from rat adipocytes.

The ability of polyamines and other cationic compounds including monoamines, amino acids, poly-L-arginine, poly-D-lysine and poly-L-lysine, to alter pyruvate dehydrogenase (PDH) activity in mitochondria from rat epididymal adipocytes was determined. PDH was assayed with the substrate [1-14C] pyruvate in the presence of 0.05 mM Ca2+ and Mg2+. Nine of the fourteen compounds tested at 0.1 mM caused a significant increase (procaine, 3-(beta-morpholinopropionyl) benzo [b]thiophene [VII], spermine, spermidine, putrescine, lysine and tryptophan) or decrease (poly-L-arginine, 3-(beta-piperidinopropionyl) benzo[b]thiophene) in PDH activity. None of these compounds nonenzymatically decarboxylated [1-14C] pyruvate to release 14CO2. NaF, a PDH phosphatase inhibitor, suppressed the stimulatory effects of those compounds tested: procaine, tryptophan, VII, spermine and spermidine. These results imply that these five compounds activate PDH activity through stimulation of the PDH phosphatase. When the Mg2+ concentration was increased from 0.05 to 4.5 mM, the stimulatory effect of spermine was increased, consistent with the finding by others that spermine lowers the Km of the enzyme for Mg2+. However, at Mg2+ concentrations greater than 0.3 mM, the stimulatory effect of VII was unaltered, procaine failed to alter PDH activity, lysine inhibited PDH activity, and poly-L-lysine stimulated PDH activity. Therefore, polyamines and other positively charged small molecules may be physiologic regulators of PDH activity.

Adipose Tissue↗
PubMed2000

On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns.

RATIONALE: Drugs that are self-administered appear to vary in their potency and effectiveness as positive reinforcers. Understanding mechanisms that determine relative effectiveness of drugs as reinforcers will enhance our understanding of drug abuse. OBJECTIVES: The hypothesis of the present study was that differences among dopamine transporter (DAT) ligands in potency and effectiveness as a positive reinforcers were related to potency and effectiveness as DA uptake inhibitors. Accordingly, self-administration of a group of local anesthetics that are DAT ligands was compared to their effects as DA uptake blockers in vitro in brain tissue. METHODS: Rhesus monkeys were allowed to self-administer cocaine and other local anesthetics i.v. under a progressive-ratio schedule. The same compounds were compared in standard in vitro DA uptake assays using monkey caudate tissue. RESULTS: The rank order of both potency and effectiveness as reinforcers was cocaine > dimethocaine > procaine > chloroprocaine. Tetracaine did not maintain self-administration. For inhibiting DA uptake, the potency order was cocaine > dimethocaine > tetracaine > procaine > chloro-procaine. At maximum, these compounds were equally effective in blocking DA uptake. Lidocaine did not inhibit DA uptake. CONCLUSIONS: The potency of local anesthetics as positive reinforcers is likely related to their potency as DA uptake inhibitors. Variation in their effectiveness as positive reinforcers was not a function of differences in effectiveness as DA uptake blockers, but may be related to relative potency over the concentrations that are achieved in vivo. Effects at sodium channels may limit the reinforcing effects of local anesthetics.

Anesthetics, Local↗
PubMed1975

Enhanced synthesis de novo of phosphatidylinositol in lymphocytes treated with cationic amphiphilic drugs.

A variety of amphiphilic cations caused very large increases in the rates of incorporation of Pi and glycerol into phosphatidylinositol in pig mesenteric small lymphocytes. This synthesis de novo of phosphatidylinositol led to a doubling of the phosphatidylinositol concentration in the cells within 3.5 h. The increase in synthesis of phosphatidylinositol labelled with [3H]- or [14C]-glycerol was matched by an approximately equivalent decrease in incorporation of glycerol into phosphatidylcholine, phosphatidylethanolamine and triacylglycerol. Amphilic cations which produced these effects included, in order of decreasing effectiveness, trifluoperazine (half-maximal effect at about 70 mum) greater than chlorpromazine approximately promethazine approximately imipramine greater than cinchocaine greater than amethocaine approximately cetyltrimethylammonium greater than fenfluramine greater than amphetamine greater than 2-phenethylamine greater than cocaine approximately procaine; the most effective compounds were those with the largest and most hydrophobic non-polar substituents. The response to cations was not changed by varying the extracellular Ca2+ concentration in the range 10 nm-1mm. The active amphiphilic cations interacted with anionic phospholipids causing aggregation of aqueous dispersions and/or changes in chromatographic behaviour. These results indicate that amphiphilic cations redirect glycerolipid synthesis de novo, probably owing to inhibition of phosphatidate phosphohydrolase, so that phosphatidylinositol synthesis is increased at the expense of other glycerolipids.

Amphetamine↗
PubMed1997

Use of identical assay conditions for cocaine analog binding and dopamine uptake to identify potential cocaine antagonists.

The addictive and euphorogenic properties of cocaine are thought to result from inhibition of the dopamine transporter (DAT). Recent evidence suggests that dopamine and cocaine bind to distinct sites on the transporter protein. Therefore it should be possible to design drugs which specifically inhibit cocaine recognition by the DAT while permitting the transporter to maintain its function of accumulating dopamine. One way to monitor such activity is to compare the inhibition constants of test agents for inhibition of radiolabelled dopamine uptake (Kiuptake) and inhibition of the binding of a cocaine ligand such as [3H]2 beta-carbomethoxy-3 beta-3 beta-(fluorophenyl)tropane (CFT; Kibind) and select for compounds with Kiuptake/Kibind ratios greater than unity. Because others have shown that compounds can exhibit Kiuptake/Kibind ratios greater than unity when the assays are performed under non-identical conditions, we have established these assays under identical conditions of time, temperature and buffer using a Chinese hamster ovary (CHO) cell line which stably expresses the human DAT. Kinetic and saturation analyses were performed on both assay and over 200 structurally diverse compounds were screened. Using identical assay parameters, several series of compounds having Kiuptake/Kibind ratios significantly greater than unity were identified. Such compounds include local anesthetics (procaine, dibucaine, tolperisone, dyclonine, diperodone), antipsychotic agents (10-(diethylaminopropionyl)phenothiazine), antidepressants (desipramine, imipramine, protriptyline), a diuretic (5-N-methyl-N-isobutyl-amilioride), an anticholinergic agent (prindinol), a PKC inhibitor (H-8), a calcium channel antagonist (loperamide) and an antimalarial compound (chloroquine). To our knowledge, even though these compounds exhibit low binding affinities (3-24 microM), they represent some of the most cocaine site-selective compounds identified to date using identical assay parameters.

Animals↗
PubMed1982

The actions of pentobarbitone, procaine and tetrodotoxin on synaptic transmission in the olfactory cortex of the guinea-pig.

1 It has been suggested that the depression of excitatory synaptic potentials produced by general anaesthetics can be attributed to a partial blockade of impulse conduction in the terminal branches of axons. This hypothesis has been tested by comparing the actions of pentobarbitone, procaine and tetrodotoxin (TTX) on synaptic transmission in the guinea-pig olfactory cortex. 2 Pentobarbitone (0.1-0.3mM) depressed the evoked synaptic potentials without any significant depression of impulse conduction in the afferent fibres of the lateral olfactory tract (1.o.t). It had no effect on the electrical excitability of either the l.o.t axons or the postsynaptic neurones. 3 Tetrodotoxin (TTX; 1-5x10(-8 M) slowed conduction of impulses in the l.o.t. and decreased the amplitude of the l.o.t compound action potential in proportion to the concentration applied. All concentrations of TTX elevated the electrical threshold of the l.o.t. axons and there was evidence to suggest that the threshold of the postsynaptic neurones was also elevated. The synaptic potentials were depressed in direct proportion to the depression of the l.o.t. compound action potential. 4 Procaine (0.1-0.5 mM) exhibited a pattern of activity intermediate between pentobarbitone and TTX. The most marked effect, seen at all concentrations tested, was a slowing of impulse conduction and a decrease in the electrical excitability of the l.o.t. axons. 5 It is concluded that general anaesthetics (exemplified by pentobarbitone) depress synaptic transmission by interfering with the processes involved in chemical transmission and not by blocking impulse conduction in the terminal branches of afferent nerves.

Animals↗
PubMed1976

Conformational aspects of the antifibrillatory activity of procaine.

The effects of procaine and four semi-rigid conformational analogs (compounds 1,2,3 and 4) were tested and compared on isolated rabbit atria. Procaine and the four analogs produced positive inotropic effects at all dose levels tested. The antifibrillatory activity of procaine and its analogs arranged in decreasing order of activity was compound 4 greater than 3 greater than 2 greater than 1 greater than procaine. The antifibrillatory activity of the compounds correlated to the distance between the ring nitrogen and the ester oxygen; that is, as the N-O distance increased the concentration required to reduce the following frequency decreased. However, the compound became more toxic as the N-O distance increased. Our data do not confirm the commonly regarded direct relationship between local anesthetic activity and antifibrillatory activity of procaine. Differences in activity displayed by the isomers of procaine could reflect differences in the ability of these analogs to bind to receptors responsible for the respective actions.

Animals↗