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PubMed1990

Human pharmacology of renzapride: a new gastrokinetic benzamide without dopamine antagonist properties.

The activity of the substituted benzamide renzapride on the upper gastrointestinal tract has been investigated. It has been shown to enhance stomach emptying in normal subjects; doses of 2 and 5 mg decreasing by 21 and 37% respectively the volume of gastric contents aspirated 80 min after a test meal. Renzapride was found to reduce the oro-caecal transit time as assessed by the lactulose/breath hydrogen method in a dose related manner from 0.2 to 5 mg; the later dose producing a 62% reduction. Finally renzapride was shown not to elevate plasma prolactin at a dose of 5 mg, a finding consistent with lack of dopamine receptor antagonism.

Adult↗
PubMed1985

An open study of remoxipride, a benzamide derivative, in schizophrenia.

Remoxipride is a novel substituted benzamide derivative with specific dopamine-(D2)-receptor blocking properties and selective action on brain mesolimbic functions. Ten inpatients with a DSM-III diagnosis of schizophrenia were treated with the drug in a 6-week open-label study. After 1 week placebo washout, the patients were given stepwise increased doses from 20 to 100 mg t.i.d. Most patients showed a clinically significant improvement; the mean scores in the Brief Psychiatric Rating Scale decreased from 25.8 at baseline to 11.3 at endpoint. Few adverse events were recorded and the rated extrapyramidal symptoms were lower at endpoint than at baseline. No abnormalities in clinical chemistry, haematology, cardiovascular assessments or EEG recordings were seen.

Adult↗
PubMed1985

Dopamine D2 receptors selectively labeled by a benzamide neuroleptic: [3H]-YM-09151-2.

In order to label dopamine D2 receptors selectively we tritiated the potent benzamide neuroleptic, YM-09151-2 (26.7 Ci/mmol). The binding of [3H]-YM-09151-2 to canine striatal membranes was saturable and specific with a KD of 57 pmol/l and Bmax of 36 pmol/g tissue as determined by Scatchard analysis. The KD, but not the Bmax, of [3H]-YM-09151-2 increased 6-fold in the absence of sodium chloride. [3H]-YM-09151-2 labeled 40% more sites than [3H]-spiperone in the same tissue homogenate. [3H]-YM-09151-2 binding was inhibited by dopaminergic drugs in a concentration and stereoselective manner with the appropriate dopamine D2 receptor profile. Thus, dopamine agonists inhibited [3H]-YM-09151-2 binding to canine striatal membranes with the following rank order of potency: (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than (-)-noradrenaline greater than serotonin greater than (-)-isoprenaline. Dopaminergic antagonists competed for [3H]-YM-09151-2 binding with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than SCH-23390 greater than (-)-butaclamol. Furthermore, dopamine agonists recognized 2 states of the receptor labeled by [3H]-YM-09151-2, Dhigh2 and Dlow2. The Dhigh2 state of the receptor could be converted to Dlow2 by guanine nucleotides and sodium ions as is the case for [3H]-spiperone binding to D2 receptors. [3H]-YM-09151-2 appears to be a more selective ligand for dopamine D2 receptors than [3H]-spiperone, since YM-09151-2 displays approximately 9-fold lower affinity than spiperone for cortical serotonergic (S2) receptors. [3H]-YM-09151-2 may become a useful tool for the selective characterization of dopamine D2 receptors.

Animals↗
PubMed1993

Dose-ranging evaluation of the substituted benzamide dazopride when used as an antiemetic in patients receiving anticancer chemotherapy.

Dazopride, a substituted benzamide structurally related to metoclopramide, is a potent gastric prokinetic agent that prevents cisplatin-induced emesis in animals. Unlike metoclopramide, dazopride has no effect on dopamine receptors and therefore should not produce extrapyramidal side effects. In this dose-ranging trial, 23 patients with cancer receiving chemotherapy known to produce nausea and vomiting received three i.v. infusions of dazopride every 2 h beginning 30 min before the chemotherapy. Seven dose levels were explored ranging from 0.5 to 4.0 mg/kg in each of the three infusions. Toxicities were mild and included sedation, dizziness, visual disturbances, and headaches. All side effects were transient and were not dose-related. Antiemetic effects were observed. Dazopride can be safely given on this schedule at doses of up to 4.0 mg/kg to patients receiving chemotherapy. On the basis of the results of this trial, further studies of this agent are warranted.

Adult↗
PubMed1992

Benzamide potentiation of the cytotoxicity of bifunctional galactitol [correction of galacticol] in resistant P388 leukemia correlates with inhibition of DNA ligase II.

Benzamide (BA) enhances the cytotoxicity of 1,2:5,6-dianhydrogalactitol (DAG) in resistant P388 leukemia cell lines but not in the sensitive parent line. To examine the reason for this difference in response, we carried out an alkaline elution assay using proteinase K to study DNA interstrand cross-linking. At early time points, equal concentrations of DAG produced the same level of interstrand cross-linking (ICL) in the resistant and sensitive P388 leukemic cells, although marked differences were observed in their cytotoxicity toward the two cell lines. In the sensitive cells, neither the amount of DNA cross-linking nor the cytotoxicity changed during the observation period (38 h) in either the presence or the absence of BA. In contrast, the elution rate of the DNA of DAG-treated resistant cells increased with time and had reached the control levels by 38 h. However, when these cells were postincubated with BA for 38 h, the elution rate of DNA was much faster than that observed for the untreated resistant cells, indicating an accumulation of DNA single-strand breaks (SSB). The SSB accumulation caused by BA was associated with an inhibition of the activity of ligase II enzyme, which was stimulated when resistant cells were treated with DAG alone. The potentiating effect of BA on the resistant cells can thus be related to the inhibiting action of BA on the DNA-rejoining enzyme, ligase II. The lack of sensitization by BA of the DAG-treated parent cell line may be attributable to the absence of DNA-SSB formation, which is necessary for ligase II activation through the stimulation of poly(ADP-ribose) synthesis.

Animals↗
PubMed1993

Characterization of the superinduction of the c-myc proto-oncogene in fibroblasts by benzamide derivatives.

In mouse fibroblasts stimulated from quiescence into proliferation by serum the induction of expression of the c-myc proto-oncogene is strongly stimulated by 3-methoxybenzamide. Similar superinduction effects are seen with related compounds such as 3-aminobenzamide and the acid analogues, 3-anisic acid and 3-aminobenzoic acid. Whereas the benzamide derivatives are inhibitors of poly(ADP-ribose) polymerase the acid analogues are not, suggesting that inhibition of this enzyme is not the basis for superinduction of the c-myc gene. Analysis of the kinetics of induction of c-myc mRNA indicates that the RNA accumulates more rapidly as well as to a higher level in the presence of serum plus 3-methoxybenzamide than with serum alone. However the stimulation is transient in both cases. Addition of actinomycin D at 30 min or 1 h after serum stimulation shows the c-myc mRNA to be stable at these times, in the presence or absence of 3-methoxybenzamide. Thus the effect of the latter on c-myc mRNA accumulation is likely to be exerted at the level of transcription or RNA processing rather than turnover of the mRNA.

3T3 Cells↗
PubMed1988

Benzamide-inhibitable alterations in spectral properties of chromatin accompany DNA repair in UVC-exposed L5178Y cells.

We examined the response of chromatin to increasing NaCl and MgCl2 concentrations in UVC-irradiated L5178Y (LY) R and S cells, using the spectral index method (Dixon and Burkholder 1985). We have found an alteration in chromatin properties 1 h after UVC-irradiation of repair proficient LY-S cells, but no change in repair deficient LY-R cells. The change was shown as lowered spectral index, indicating that at given Na+ and Mg++ concentrations (1 or 200 mM NaCl, 0 or 0.5 mM MgCl2) chromatin from UVC-irradiated LY-S cells was more compact than that from unirradiated ones. Benzamide treatment reversed the effect of UVC-irradiation in LY-S cells and did not change the response pattern of chromatin from LY-R cells or unirradiated LY-S cells.

Animals↗
PubMed1998

Modulation of bone mass, strength, and turnover by a new benzamide compound, DU-6712, in adjuvant-induced arthritic rats.

To assess the reductions in bone mass, strength, and turnover in adjuvant-induced arthritic rats and to examine the effect of a new benzamide compound, DU-6712, on these parameters, a 28-day dosing experiment was performed using 8-week-old female Lewis rats. Arthritis was induced by injecting the adjuvant into the hind paw. The age-dependent increases in the body weight, lumbar bone mineral content and density (BMC and BMD) and compressive strength were disturbed in the arthritic rats. At 14 days, the histomorphometric parameters of bone formation (BFR/BS and BFR/BV) and the serum osteocalcin levels were significantly reduced compared with the baseline controls. However, the BMC values corrected for body weight did not differ significantly between the arthritic and normal rats, and the bone minerals were not reduced compared with the baseline controls. At 28 days, the parameters of bone minerals and strength of the lumbar body in the arthritic rats, both with and without correction for body weight, were significantly reduced compared with the baseline controls. The trabecular mineralizing surface remained significantly reduced and the osteoclast numbers were increased. DU-6712 at the doses of 5, 15, and 45 mg/kg, orally administered daily from the start of the experiment, significantly prevented the development of the chronic paw edema at 28 days. The reductions in the parameters of bone minerals, strength, and trabecular bone formation, and the increase in osteoclast number were alleviated by this agent. Age-dependent increases in the lumbar height, disturbed by the adjuvant injection, were also maintained. These data indicated that a 28-day period is necessary to obtain sufficient reductions in the bone mass and strength of the lumbar body concerning the model of secondary osteoporosis in adjuvant arthritic rats. DU-6712 was able to prevent these reductions by modulating the bone turnover in this arthritis model.

Animals↗
PubMed1999

Limited sensitivity of iodine-123-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl ] benzamide whole-body scintigraphy in patients with malignant melanoma: a comparison with thallium-201 imaging.

The aim of this prospective study was to assess the diagnostic value of iodine-123-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide (IBZM) whole-body imaging in comparison to thallium-201 scintigraphy in patients with metastatic malignant melanoma. Ten patients with suspected or proven locoregional metastases of malignant melanoma underwent whole-body scintigraphy both with 201Tl and 123I-IBZM prior to scheduled surgery. Whole-body scans and planar scintigrams were acquired at 5 min and 30 min after injection of 100 MBq 201Tl and at 10 min, 2 h, 4 h and 24 h after injection of 185 MBq 123I-IBZM. Ten out of 12 melanoma metastases, both melanotic and amelanotic as proven histologically, were detected by 201Tl with a sensitivity of 83%. 123I-IBZM showed tracer uptake only in 3 melanotic metastases (sensitivity: 25%) with a maximum tumor-to-background ratio within 4 h, while none of the amelanotic metastases was IBZM-positive. All lesions localized by 123I-IBZM showed tracer uptake of 201Tl as well, while 201Tl-negative lesions were also negative with IBZM. Because of the poor results of IBZM, the study was terminated after an interim evaluation of 10 patients. 123I-IBZM is a tracer with only moderate sensitivity in melanotic melanoma lesions, suggesting that this method has no clinical value as a routine investigation in melanoma patients. In comparison, our previous results with 201Tl whole-body scintigraphy yielded a significantly higher sensitivity of about 80% in patients with locoregional melanoma metastases and may thus offer considerable potential in non-PET melanoma imaging.

Adult↗
PubMed1996

Modulation of the effect of camptothecin in x-irradiated L5178Y-R and L5178Y-S cells by benzamide.

The L5178Y (LY) murine lymphoma subline, LY-R, is more radioresistant and more sensitive to camptothecin (CPT, inhibitor of topisomerase I) than the second subline used in our investigation, LY-S. Post-irradiation treatment with 3 microM CPT enhanced the radiosensitivity of LY-S cells (D0 decrease from 0.52 to 0.34 Gy), but did not change it in LY-R cells. Treatment with 2 mM benzamide [BZ, inhibitor of poly (ADP-ribosylation)] before x-rays and CPT increased the radiosensitivity of LY-R cells (D0 decrease from 1.15 to 0.52) without further modification of radiosensitivity of LY-S cells. Activity of topoisomerase I was diminished 10 min after x-irradiation (5 Gy) in LY-S, but not in LY-R cells. The data on DNA damage (fluorescent halo or comet assays) showed that the ultimate fate of the cells did not depend on the DNA damage pattern estimated immediately after treatment (e.g. the damage was greater in x-rays plus CPT than in BZ plus x-rays plus CPT treated LY-R cells, although the radiosensitivity was less). Aphidicolin (inhibitor of DNA polymerases alpha and delta) applied concomitantly with CPT in cells not pretreated with BZ prevented the increase in DNA damage in LY-R cells, but was without effect in LY-S cells. Taking into account the differential inhibition by x-rays of DNA synthesis in LY sublines and its reversion by BZ in LY-S but not in LY-R cells, we conclude that the pattern of DNA damage observed by the methods applied depended on the status of DNA replication.

Animals↗
PubMed2006

Laccase-induced derivatization of unprotected amino acid L-tryptophan by coupling with p-hydroquinone 2,5-dihydroxy-N-(2-hydroxyethyl)-benzamide.

We have studied the enzymatic derivatization of amino acids by use of the polyphenol oxidase laccase. Derivatization of L-tryptophan was achieved by enzymatic crosslinking with the laccase substrate 2,5-dihydroxy-N-(2-hydroxyethyl)-benzamide. The main product (yield up to 70%) was identified as the quinoid compound 2-[2-(2-hydroxy-ethylcarbamoyl)-3,6-dioxo-cyclohexa-1,4-dienylamino]-3-(1H-indol-3-yl)- propionic acid and demonstrates that laccase-catalyzed C-N-coupling occurred on the amino group of the aliphatic side chain. These enzyme based reactions provide a simple and fast method for the derivatization of unprotected amino acids.

Benzamides↗
PubMed1985

Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain.

The substituted benzamide drug raclopride, [((-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate; FLA 870(-); A40664] was shown to be a potent and selective antagonist of dopamine D-2 receptors by its high affinity for striatal 3H-spiperone binding sites and low potency to block dopamine stimulated adenylate cyclase in vitro. In vitro studies showed that 3H-raclopride binds with a high affinity (KD = 1.2 nM) and a low proportion of non-specific binding to rat striatal homogenates. The binding of 3H-raclopride is saturable (Bmax = 23.5 pmoles/g wet wt) and reversible (dissociation half-time = 30 min) with a regional distribution of the specifically bound drug showing the following rank-order: striatum greater than nucleus accumbens greater than olfactory tubercle greater than septum greater than hypothalamus greater than hippocampus greater than frontal cortex. After in vivo administration, 3H-raclopride accumulates preferentially in dopamine rich brain areas with approximately 10 times higher levels in the striatum than in the cerebellum, when examined 30 min after injection. The in vivo binding of 3H-raclopride was saturable, reversible and showed a low component of non-specific binding. More than 90% of the drug reached the brain in a non-metabolized form as judged by thin-layer chromatography. Pharmacological analysis of 3H-raclopride binding showed that it could be displaced by dopamine agonists and antagonists but not by serotoninergic or noradrenergic drugs. Taken together, the results suggest that 3H-raclopride labels dopamine D-2 receptors with high specificity in the rat brain both in vitro and in vivo, and thus, that it should be a useful tool in studies of central dopamine D-2 receptors.

Adenylyl Cyclases↗
PubMed1980

Sodium-dependent interaction of benzamides with dopamine receptors.

Sulpiride and other benzamide (BM)-displacing activity on [3H]-spiroperidol ([3H]SPIR) binding by rat striatal dopaminergic receptors was found to be uniquely sodium-dependent, while classical neuroleptic (NL) activity was not influenced by NaCl. These results suggest the existence of at least two populations of striatal dopaminergic receptors, sodium-dependent and sodium-independent, through which BM and NL respectively interact.

Animals↗
PubMed1978

Benzamides and classical neuroleptics: comparison of their actions using 6 apomorphine-induced effects.

The effects of 6 benzamides and 8 classical neuroleptics were studied on 6 different apomorphine-induced effects. These drugs did not antagonize all the effects in the same way. The differences are discussed according to the two types of dopaminergic receptor hypothesis. Some apomorphine-induced effects (stereotyped behavior, circling behavior, climbing behavior, and increased motor activity) could be related to stimulation of one type of dopaminergic receptor, other effects (hypothermia and decreased activity) to the other type. Pimozide, sulpiride, thioproperazine, GRI 1665 and TER 1546, could block selectively one type of dopaminergic receptor, at least in a given range of doses. Clozapine, chlorpromazine, levomepromazine, and thioridazine, could block selectively the other type of dopaminergic receptor. Haloperidol, metoclopramide, prochlorperazine, sultopride, and tiapride, could block both types of dopaminergic receptors with equal intensity whatever the dose.

Animals↗
PubMed1980

The effects of substituted benzamides on frog rectus abdominis.

The substituted benzamides metoclopramide, bromopride, tiapride and sulpiride (10(-5) and 10(-4) M) significantly increased the sensitivity of frog rectus abdominis muscle to exogenous acetylcholine but not to carbachol. This supersensitivity could be correlated with the anticholinesterase activity of these drugs measured in homogenates from frog skeletal muscle. Sultopride, like procainamide, has only inhibitory effects on the responses of the rectus abdominis to acetylcholine and has no anticholinesterase activity in this preparation.

Amisulpride↗
PubMed1984

Neuronally mediated contraction responses of guinea-pig stomach smooth muscle preparations: modification by benzamide derivatives does not reflect a dopamine antagonist action.

The actions of the substituted benzamide derivatives metoclopramide, clebopride, YM-09151-2, tiapride, (+)- and (-)-sulpiride and (+)- and (-)-sultopride, and the dopamine antagonists haloperidol and domperidone, were studied on the responses to field stimulation (0.125-10 Hz) of smooth muscle strips taken from cardia, fundus, body and antral regions of the longitudinal and circular muscle of guinea-pig stomach. Field stimulation of the longitudinal strips caused contraction responses which were antagonised by atropine (but not by prazosin, yohimbine, propranolol or methysergide) to indicate a muscarinic cholinergic involvement. Antagonism of the contractions revealed or enhanced relaxation responses mediated via unidentified mechanisms (resistant to cholinergic and adrenergic antagonists). Metoclopramide enhanced the field stimulation-induced contractions of the stomach smooth muscle preparations via atropine sensitive mechanisms but failed to attenuate the field stimulation-induced relaxation responses. Clebopride's action closely followed that of metoclopramide but YM-09151-2 only enhanced the contraction responses of the longitudinal muscle preparations. Other dopamine antagonists, (+)- and (-)-sulpiride, (+)- and (-)-sultopride, tiapride, haloperidol and domperidone failed to facilitate contraction to field stimulation of any stomach tissue. Thus, the actions of metoclopramide, clebopride and YM-09151-2 to facilitate contraction to field stimulation of stomach smooth muscle are mediated via a muscarinic cholinergic mechanism and are not the consequence of an antagonism at any recognisable dopamine receptor.

Animals↗
PubMed1996

Reversion in Chinese hamster lines amplified at the AMPD2 locus: spontaneous and benzamide-stimulated gradual loss of amplified alleles of marker genes.

The HC47 and HC474 cell lines of Chinese hamster fibroblasts resist coformycin through the intrachromosomal amplification of the AMP deaminase 2 (AMPD2) gene. Due to the coamplification of a mu glutathione S-transferase (GST) gene, these mutant lines are more sensitive than GMA32 wild-type parental cells to buthionine sulfoximine (BSO), an inhibitor of glutathione biosynthesis. This property was exploited to select revertants of amplification from HC474 cells. Reversion in that line is frequently a gradual process that does not involve extrachromosomal intermediates. The terminal products of this process are commonly cells with a complete deletion of the amplified allele of marker genes and are therefore haploid for these loci on the homologous chromosome. Exposing HC474 cells to benzamide (BA), an inhibitor of polyADP-ribosylation, increased the recovery of revertants to an extent allowing the detection of reverting cells without BSO selection. This effect of BA was used to isolate revertant cells from the HC47 line that is extremely stable and to demonstrate that the mechanism of gradual reversion also occurs in this line. The gradual deletion of amplified copies within the chromosomes suggests that breakage-fusion-bridge (BFB) cycles drive this process.

AMP Deaminase↗