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PubMed2003

Direct determination of benzamides in serum by column-switching high-performance liquid chromatography.

A column-switching high-performance liquid chromatographic method with fluorescence detection was developed for the simultaneous determination of four benzamide-type anti-psychotic drugs: sulpiride, tiapride, sultopride and metoclopramide in human serum. In this method, a TSKgel Super-ODS column was used as an analytical column, and a TSKgel G 2000SW was prepared as a pretreatment column. Under the optimized analytical conditions, four benzamide-type anti-psychotic drugs were eluted within 18 min. The detection limits (S/N = 3) for sulpiride, tiapride, sultopride and metoclopramide are 1 ng/ml, 4 ng/ml, 2 ng/ml and 0.5 ng/ml, respectively. Finally, the method was applied to the determination of sulpiride in human serum samples obtained after a single oral dose of sulpiride.

Benzamides↗
PubMed1986

Comparative pharmacokinetics of a new benzamide neuroleptic drug in rats, dogs and monkeys using a stable isotope technique.

Comparative pharmacokinetics of a new benzamide neuroleptic drug, cis-N-(1-benzyl-2-methylpyrrolidine-3-yl)-5-chloro-2-methoxy-4-met hylamino benzamide (NBND) was studied in rats, dogs and monkeys using two deuterium-labelled compounds. NBND and 2H3-NBND, which showed no biological isotope effect, were co-administered p.o. and i.v. to rats, dogs and monkeys, and the plasma concentrations of unchanged drugs were simultaneously determined by g.l.c.-chemical ionization mass spectrometry with 2H7-NBND as an internal standard. The plasma half-lives (t1/2 beta) after i.v. administration were 1.6, 4.7 and 2.2 h in rats, dogs and monkeys at a dose of 0.2 mg/kg. Plasma clearances were 4.3, 1.7 and 1.4 l/h per kg in rats, dogs and monkeys. Absorption rate constants (Kab) were 1.1, 0.58 and 0.54 per h in rats, dogs and monkeys, at doses of 10, 3 and 5 mg/kg, respectively. Absolute bioavailabilities were 0.8, 9.5 and 1.3% in rats, dogs and monkeys, suggesting that all these species showed large first-pass effects, probably due to hepatic metabolism.

Administration, Oral↗
PubMed1988

Differential effect of benzamide on NAD+ content and the frequency of chromatid aberrations in X-irradiated L5178Y-R and L5178Y-S cells.

The effect of treatment with benzamide, an inhibitor of adenosine diphosphate (ADP) ribosyl polymerase (ADPRP) was studied in cells of two strains of L5178Y (LY) murine lymphoma exposed to ionizing radiation. Continuous 2 mmol/l benzamide (Bz) treatment increased the frequency of chromatid aberrations in the radiation sensitive LY-S strain, but not in the resistant LY-R strain. This result is in agreement with the previously found, enhanced by Bz, killing effect of roentgen irradiation in LY-S cells. Also, the decrease in the cellular NAD+ content in these cells after irradiation was more pronounced than in LY-R cells; this may indicate an increased ADPRP activity upon infliction of DNA damage, or a difference in poly(ADP-ribose) turnover.

Animals↗
PubMed1975

[Comparative study on the action of some substituted benzamides on the isolated ileum of the guinea pig].

Metoclopramide [(Mcp)-N-diethylaminoethyl-2-methoxy-4-amino-5-chloro-benzamide] was shown by the authors (This Journal 1973, 204, 239) to stimulate the isolated guinea-pig ileum, mainly by an indirecr cholinergic mechanism, to increase responses to acetylcholine (Ac) and transmural stimulation, and to inhibit responses to serotonin (5 HT) and histamine (H). Four structuraly related benzamide derivative (1211, 1265, 1308 and 1347) also stimutated the ileum, 1211 being the most active, and 1347 the least active, and resembled Mcp with regard to the responses to Ac, transmural stimulation and histamine. However, serotonin contractions were enhance by 1265 and 1347, while 1308 and 1211 were inhibitory. These observations suggest that a 4-amino group does not seem to be essential for the stimulant effect or the interference with Ac responses (1211, 1265, 1347), whereas a methylsulfonyl group (1347) and, to a lesser degree, a flour in 5 position (1265) sensitize the ileum towards 5 HT contractions.

Acetylcholine↗
PubMed1991

High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides.

Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. "Iodopride" (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, "iclopride" (KD 0.23 nM) and "itopride" (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, "epidepride" (KD 0.057 nM) and "ioxipride" (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

Animals↗
PubMedDate not supplied

[The search for new antiparasitic agents. 1. The synthesis and study of the acute toxicity of new halogen-containing benzamides].

The paper presents the results of toxicological study of 44 compounds of the benzamide series synthesized during search for new anthelminthic agents. The dependence of the toxic effect of the benzamides synthesized on their structure is analysed. The experiments were carried out on white mice given the compounds under study once orally. The maximum tolerated doses of the compounds are presented. It has been found that 34 out of 44 compounds have a low toxicity and are worth of further anthelminthic screening.

Animals↗
PubMedDate not supplied

[Recovery from potentially lethal damage of irradiated L5178Y-R and L5178Y-S cells: the effect of temperature and benzamide].

Mouse lymphoma L5178 Y-S and Y-R cells differing in radiosensitivity by 1.5 times were treated with benzamide, an inhibitor of poly(ADP-ribosylation), for 24 h before and 18 h after X-irradiation, and incubated after irradiation at 25 degrees C and 37 degrees C. Clonogenic capacity of LY-S cells incubated at 25 degrees C exceeded that of the same cells incubated at 37 degrees C; the clonogenic capacity of LY-R cells did not vary with the postirradiation incubation temperature. Benzamide increased equally the radiosensitivity of LY-R cells incubated at both temperatures, whereas that of LY-S cells was only increased at 37 degrees C. Repair of potentially lethal damages to LY-S cells incubated at 25 degrees C was independent of the effectiveness of poly(ADP-ribosylation).

Animals↗
PubMedDate not supplied

Metabolism of the prodrug DEGA (N-(2,6-dimethylphenyl)-4-[[(diethylamino)acetyl]amino]benzamide) to the potent anticonvulsant LY201116 in mice. Effect of bis-(p-nitrophenyl)phosphate.

In mice, the diethylglycineamide analogue of LY201116, DEGA (N-(2,6-dimethylphenyl)-4-[[(diethylamino)acetyl]amino]benzamide), is metabolized by consecutive N-deethylations for form MEGA and GA; the monoethylglycineamide and glycineamide analogues of LY201116, respectively. All of these compounds are in turn hydrolyzed to form LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide]. LY201116 is N-acetylated to form the N-acetyl metabolite, NAC. NAC is also deacetylated to reform LY201116. All of the above compounds inhibit maximal electroshock-induced seizures (MES) in mice. After oral administration, the potencies of these compounds were similar at their time of peak anticonvulsant effect. However, the MES ED50 values for the above compounds 5 min after iv dosing were 43, 13, 2, and 0.5 mg/kg for DEGA, MEGA, GA, and LY201116, respectively. Similar plasma levels of LY201116 were produced in mice 5 min after iv dosing with the respective ED50 values of the above compounds, which suggested that all of the compounds produced their anticonvulsant effects via LY201116. The in vivo metabolism of DEGA and MEGA but not GA to LY201116 was inhibited by the acylamidase inhibitor bis-(p-nitrophenyl) phosphate (BNPP). Mice predosed with BNPP were not protected by DEGA and MEGA from MES-induced seizures and the plasma samples contained little or no LY201116. The metabolism of GA to LY201116 was not inhibited by BNPP, and GA was an active anticonvulsant in BNPP-pretreated mice. The apparent iv potency of DEGA increased dramatically with time after dosing, again suggesting time-dependent, metabolically mediated liberation of the more potent anticonvulsant LY201116.

Animals↗
PubMed1987

Analogues of benzamide containing a sulfur atom as poly(ADP-ribose) transferase inhibitors.

Structural analogues of benzamide (BA) containing a sulfur atom were tested for their ability to inhibit the enzyme poly(ADP-ribose)transferase (ADPRT) in cultured Chinese Hamster Ovary (CHO) cells. These compounds were benzene sulfonamide (BSA), thiobenzamide (TB) and 3-thiophene carboxamide (TCA) and their activity was compared with that of benzamide in a number of experimental systems. Results have shown that substitution of the carboxamide function with a sulfonamide group produces an almost complete loss of the enzyme inhibiting activity. Also inactive was TB which however was found to display inhibition of the DNA damaging effect of hydrogen peroxide, thus suggesting a hydroxyl radical scavenging effect of TB. TCA, an isostere of BA, produced some inhibition of ADPRT, although its activity was markedly lower than that of the parental drug. Therefore, these results indicate that: 1) ADPRT inhibiting activity is inverse function of dipole moments, hydrogen bonding strength and steric hindrance of the amide functional group and 2) substitution of benzene with thiophene results in a substantial reduction of the enzyme inhibiting activity.

Animals↗
PubMed1986

[Effect of benzamide derivatives on rat brain monoamine oxidase activity in vitro].

The ability of moclobamide and other benzamide derivatives to inhibit the activity of monoamine oxidase in the rat brain was studied. Distinct effects of these compounds on the deamination of serotonin and norepinephrine (MAO-A substrates); 2-phenylethylamine (selective MAO-B substrate); tyramine and dopamine (MAO-A and MAO-B substrates) are shown. It was demonstrated that among all the compounds studied moclobamide appeared to be the most active and selective inhibitor of MAO-A: at a concentration of 100 microM it caused a 100% inhibition of serotonin and norepinephrine deamination, which might be explained by the presence of C1 atom in the para-position of benzene ring in moclobamide molecule. Other benzamide derivatives were less active in inhibiting MAO-A and had but a negligible effect on dopamine- and 2-phenylethylamine deamination.

Animals↗
PubMed1983

[Biochemistry and pharmacology of benzamides].

The pharmacologic characteristics of the action of benzamide derivatives on the central nervous system are discussed, with sulpiride as the reference agent. The pharmacologic study of sulpiride includes the study of its effects on animal behaviour and of the biochemical modifications in the central monoaminergic systems. In animals, sulpiride has a strikingly atypical action, with no cataleptigen effects except at high dosages, a dissociated antagonism towards the effects of apomorphine and activating effects at low dosages. A dissociated antagonism towards the effects of sulpiride on the central monoaminergic receptors results in a typical neuroleptic pattern at high dosages, with a predominating action on mesolimbic structures at low dosages. As for its action on central dopaminergic receptors, sulpiride shows a high affinity for mesolimbic structures and for structures which are not included in the blood-brain barrier: it has no effect on DA receptors bound to adenyl-cyclase; it activates at low dosages (by blocking inhibiting receptors) and inhibits at high dosages (by blocking activating receptors); it has no extrapyramidal effects; according to Schwartz, Costentin et al., it would block D2 and especially D4 receptors in the mesolimbus and striatum at low dosages and striatal D2 receptors at high dosages. In the last chapter, the other benzamide derivatives are discussed relatively to sulpiride.

Animals↗
PubMed1982

Clinical trials of benzamides in psychiatry.

The utility of the benzamides in clinical psychiatry requires further evaluation. Of the four compounds mentioned in this chapter, it seems clear that sulpiride is an effective antipsychotic agent as shown by double-blind trials comparing it with placebo and reference antipsychotics (see Table I). Claimed efficacy for this agent in depression, anxiety, and school-phobia require more intensive evaluation. Sultopride has been reported to have efficacy in a variety of psychiatric syndromes, i.e., manic depressive illness and agitation associated with alcoholic syndromes. Tiapride has reported efficacy in a variety of alcoholic states, agitation associated with medical disease, and movement disorders. Unfortunately, all of the studies on both tiapride and sultopride have been open trials on which the results were based solely on the global clinical impression of the investigator. The total lack of formal diagnostic criteria, adequate study design, small sample size, heterogeneity of diagnosis, and questionable length of time for treatment of these disorders make it impossible to draw any firm conclusions at this time as to the efficacy toward any psychiatric disorder. Metoclopramide, on the other hand, may not only have possible antipsychotic efficacy based on one open study (62,63) but may provide an important clue as to the action of antipsychotics in general. More double-blind studies are indicated to assess its function in acute psychosis. The four compounds do seem to have properties similar to many of the classic antipsychotic agents in view of their common dopamine-blocking activity, antiemetic, sedative, and cataleptic effects. In addition, they have similar spectrum of side effects. Certain effects such as lack of efficacy in dopamine receptor models (for metoclopramide) and questionable differences in sites of action (blocking of dopamine and mesolimbic versus nigral striatal areas for sulpiride) may indicate unique neurochemical effects for these compounds and may provide a clue to allow the investigators to better predict antipsychotic efficacy and draw inferences regarding sites of action and mechanisms underlying neuroleptic activity. The benzamides have been used extensively in France since 1967. Before these drugs can be considered to be effective antipsychotic agents on par with phenothiazines and butyrophenones, further double-blind studies are indicated. These studies would give us a better idea as to whether they fit into the psychiatrist's armanentarium and may allow further insights into the relationship between descriptive psychopathology and neuropharmacology.

Amisulpride↗
PubMed1983

The filaricidal activity of some derivatives of N-[2-(4-thiazolyl)benzimidazol-5-yl]benzamide against Brugia pahangi adults.

A series of analogues of N-[2-(4-thiazolyl)benzamidazol-5-yl]benzamide with halogen substituents on the benzamide ring was tested for activity against adult Brugia pahangi in the peritoneal cavities of jirds. None of the chloro, bromo or iodo analogues was active at 5 x 100 mg/kg by subcutaneous injection. The 2-fluoro, 3-fluoro and 4-fluoro analogues showed greater activity than the parent compound and the 2,5-difluoro analogue had the same activity as the parent. The 3-fluoro, 4-fluoro and 2,5-difluoro analogues were not active in cats treated per os with 5 x 50 mg/kg.

Animals↗
PubMed1978

Pharmacological analysis of the effects of substituted benzamides on the isolated guinea-pig ileum. Study of metoclopramide, sulpiride, bromopride, tiapride and sultopride.

The effects of metoclopramide (Mcp), sulpiride (Sp) and some of their derivatives: bromopride (Br), tiapride (Ti) and sultopride (Stp) have been compared on the guinea-pig isolated ileum. 1. Br and Ti have, like Mcp, and indirect cholinergic stimulating effect on the intestinal smooth muscle. Sp and Stp are devoid of such an effect. 2. At high doses, all the benzamides have a direct inhibitory effect on the ileum. 3. Mcp, Br and Ti (10(-5)M) potentiate the responses of the ileum to acetylcholine (ACh). At high doses (10(-4)M) the effects of all benzamides on the responses to ACh as well as to histamine (H) are mostly inhibitory. 4. Mcp and Br (10(-5)M) inhibit the responses of the ileum to serotonin (5HT) while Ti, Sp and Stp potentiate them. 5. Neural pathways and calcium mechanisms are involved in the potentiations of ACh and 5HT responses since the enhancements observed are abolished in the presence of tetrodotoxin or in the absence of Ca++.

Acetylcholine↗
PubMed2003

Hierarchical self-assembly, coassembly, and self-organization of novel liquid crystalline lattices and superlattices from a twin-tapered dendritic benzamide and its four-cylinder-bundle supramolecular polymer.

The synthesis and structural analysis of the twin-dendritic benzamide 10, based on the first-generation, self-assembling, tapered dendrons 3,4,5-tris(4'-dodecyloxybenzyloxy)benzoic acid and 3,4,5-tris(4'-dodecyloxybenzyloxy)-1-aminobenzene, and the polymethacrylate, 20, which contains 10 as side groups, are presented. Benzamide 10 self-assembles into a supramolecular cylindrical dendrimer that self-organizes into a columnar hexagonal (Phi(h)) liquid crystalline (LC) phase. Polymer 20 self-assembles into an imperfect four-cylinder-bundle supramolecular dendrimer, and creates a giant vesicular supercylinder that self-organizes into a columnar nematic (N(c)) LC phase which displays short-range hexagonal order. In mixtures of 20 and 10, 10 acts as a guest and 20 as a host to create a perfect four-cylinder-bundle host-guest supramolecular dendrimer that coorganizes with 10. A diversity of Phi(h), simple rectangular columnar (Phi(r-s)) and centered rectangular columnar (Phi(r-c)), superlattices are produced at different ratios between 20 and 10. This diversity of LC lattices and superlattices is facilitated by the architecture of the twin-dendritic building block, polymethacrylate, the host-guest supramolecular assembly, and by hydrogen bonding along the center of the supramolecular cylinders generated from 10 and 20.

Journal Article↗
PubMed1985

Some in vitro receptor binding properties of [3H]eticlopride, a novel substituted benzamide, selective for dopamine-D2 receptors in the rat brain.

The substituted benzamide compound eticlopride, (S)-(-)-5-chloro-3-ethyl-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide hydrochloride (FLB 131), has been shown to selectively block dopamine-D2 binding sites in the rat brain. The compound was tritium-labelled to high specific radioactivity and was used for in vitro receptor binding studies. [3H]Eticlopride was found to bind specifically to rat brain homogenates with the highest binding in the striatum and lowest in the hippocampus. The binding was saturable with a high number of binding sites (49.5 pmol/g) and with very high affinity (0.17 nM). As with other benzamides, the binding of [3H]eticlopride was highly sodium-dependent. Lesioning of the striatal neurons with ibotenic acid reduced the binding by 50% while lesioning of the nigrostriatal pathways with 6-hydroxydopamine was without effect on the observed binding. The binding of [3H]eticlopride was inhibited potently by neuroleptic drugs, while compounds known not to interact with the dopamine-D2 binding sites were inactive. It is concluded that this new dopamine-D2 antagonist may be a useful tool for the study of dopamine-D2 binding sites due to its high affinity and good selectivity.

Animals↗
PubMed1986

Regional in vivo binding of the substituted benzamide [3H]eticlopride in the rat brain: evidence for selective labelling of dopamine receptors.

The novel substituted benzamide eticlopride, (S)-(-)-5-chloro-3-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxy salicylamide hydrochloride (A38503; FLB 131), was radiolabelled to high specific activity and used for in vivo receptor binding studies in the rat brain. Intravenous injections of [3H]eticlopride resulted in a rapid accumulation of radioactivity in several brain regions: striatum greater than olfactory tubercle greater than septum greater than substantia nigra greater than frontal cortex greater than cerebellum. Approximately 95% of the radioactivity recovered from the striatum was in the form of authentic eticlopride, as determined by thin-layer chromatography. Two hours after injection, the ratio between the amount of radioactivity present in the striatum and in the cerebellum was approximately 10:1. The in vivo binding of [3H]eticlopride was saturable in all dopamine-rich areas, with a very low proportion of non-specific binding. The specific in vivo binding of [3H]eticlopride was blocked by several dopamine antagonists, including haloperidol, (+)-butaclamol, spiperone, d,l-sulpiride and remoxipride. The dopamine agonist N-n-propylnorapomorphine, but not apomorphine, was found to be a potent blocker of in vivo [3H]eticlopride binding. Serotonin and noradrenaline receptor antagonists did not prevent the in vivo binding of [3H]eticlopride. Autoradiographic analysis of the in vivo [3H]eticlopride binding showed a high density of binding sites in the striatum, nucleus accumbens and the olfactory tubercle. Moderate binding was found in the hippocampal formation and in the entorhinal area, but little or no binding was detected in other cortical regions. [3H]Eticlopride binding in all these areas was blocked by pretreatment with (+)-butaclamol. Taken together, these findings show that the substituted benzamide compound [3H]eticlopride passes readily into the brain and binds with high specificity to dopamine or neuroleptic receptors in dopamine-rich brain areas. Thus, eticlopride may be a useful tool in studies of dopamine D-2 receptors in vivo.

Animals↗