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PubMed1988

Effect of some benzamide derivatives on stress-induced behavior and striatum dopamine receptors.

The effects of a new benzamide derivative LIS-630 and the well-known neuroleptic, tiapride, were studied on stress-induced hyper- and hypoactive emotional behavioral reaction of animals depending on the individual ability for perceptive-cognitive activity in stress situations, and their affinity to striatal DA receptors. A modified variant of forced swimming method was used. The affinity of the substances to striatal DA receptors was studied by the radioligand binding method using 3H-spiroperidol. The results show that the psychopharmacological profile of LIS-630 differs significantly from the neuroleptic, tiapride. LIS-630 restored escape behavior from stress situation after preliminary exposure of rats to forced swimming and did not disturb escape behavior in animals more resistant to emotional hypoactivity. LIS-630 reduced immobility time at forced swimming. However, it is not effective in preventing hyperemotional reactions induced by L-dopa and stress. The radioligand binding study shows that LIS-630 did not displace 3H-spiroperidol from the binding sites of striatum membranes. The parameters of displacement with tiapride were satisfactory.

Animals↗
PubMed1987

[Effect of benzamide derivatives on convulsions induced by the toxic action of oxygen in rats].

The reversible MAO-A inhibitor moclobemide (5 mg/kg) was shown to prevent seizures in rats during exposure to toxic oxygen (6 ata). Benzamide derivatives increased the latent period of oxygen seizures and decreased the lethality following hyperbaric oxygenation. The range of anti-MAO activity of moclobemide and clorgyline in the rat brain and heart after toxic oxygenation was studied. It was distinct from those in control animals. Clorgyline was found to be more active in inhibiting MAO during toxic oxygenation in the heart and moclobemide-in the brain. The possibility is shown to prevent oxygen seizures not only with irreversible MAO-A inhibitors (clorgyline), but also with reversible ones (moclobemide).

Animals↗
PubMed1978

Binding study of benzamides to serum albumins by fluorescence probe technique.

The interaction between human and bovine serum albumins (HSA and BSA) were studied with two derivatives of benzamide, metoclopramide (Primpéran) and sultopride (Barnétil). It was possible to evaluate association constants (K ass.) characterising this interaction by fluorescence probe technique inspite of the very low binding tendency, which can be correlated to pharmacokinetic properties of these drugs.

Animals↗
PubMed1983

Neuropharmacological profile of MD 790501, a new benzamide derivative.

Using several classical screening procedures in different species MD 790501: (exo)-2,3 dimethoxy-N-[8-(phenylmethyl)-8-azabiocyclo [3.2.1]oct-3-yl] benzamide hydrochloride was shown to possess potent neuroleptic properties. The doses effective in the tests for neuroleptic activity were similar to or lower than those for heloperidol and clearly lower than those for bromopride, chlorpromazine, sulpiridie, sultopride and thioridazine. Compared with the reference compounds tested MD 790501 showed sedative, cataleptic and dyskinetic effects at doses relatively higher than those effective in tests for neuroleptic activity. MD 790501 possessed no noradrenolytic, anticholinergic, proconvulsant or anxiolytic activity. Its acute toxicity was in the same dose range as that of reference neuroleptics.

Animals↗
PubMed1975

[Substituted benzamides].

The comparison of the therapeutic effects of three molecules belonging to the substituted benzamide family allows the following observations: --the three products are generally well tolerated by the organism; --at sufficient doses they act as a major tranquilizers: -sulpiride is chiefly a disinhibitor but also has antipsychotic properties; -sultopride is at first somewhat sedative, especially when given parenterally, then antipsychotic, and little by little desinhibiting; -GRI 16-65 is "soothing", "euphoriant", "sociabilizing", as well as antipsychotic. Effect of reintegration in reality seems to constitute a common characteristic of these three products.

Antipsychotic Agents↗
PubMed1982

The substituted benzamides in gastroenterology.

The gastrointestinal tract possesses an intrinsic nervous system whose morphology, function, and neuropeptides show many similarities to those of the brain. The central nervous system and the gut's intrinsic nervous plexus are linked together by a network of extrinsic nerve fibers. The majority of these nerve fibers are afferent and relate messages from the gut to the central nervous system. The remainder are efferent fibers which can excite or inhibit gut activity by influencing mechanisms within the intrinsic nervous plexus. Many syndromes of altered gut activity are ascribed to psychosomatic factors, and treatment of these disorders is frequently directed at the central nervous system. Although substituted benzamides act on the central nervous system, enforcement of central nervous control of gut activity does not seem relevant to their clinical efficacy and little is known about their effect on sensations originating in the gut. It is tempting to ascribe similar activities for these agents both in the gut and in the brain. Nevertheless, it appears that cholinergic rather than antidopaminergic mechanisms govern the peripheral actions of these agents.

Benzamides↗
PubMed1982

Synthesis of substituted benzamides and benzimidazoles as anthelmintic and antimicrobial agents.

The synthesis and biological activity of a series of substituted benzamides (5-8, 14-17) 3,5-dinitrobenzoic acids (12, 13, 18) and benzimidazoles (9-11, 19-21) are described. Compounds 5, 6, 7, 12 and 14 showed 40-50% clearance of Nippostrongylus brasiliensis in rats at a dose of 250 mg/kg given daily for 3 d while a few compounds inhibited the growth of various strains of bacteria and fungi.

Animals↗
PubMedDate not supplied

[Four benzamides (metoclopramide, sulpiride, sultopride and tiapride) effects on the oestrus cycle of the female rat: a comparative statistical study (author's transl)].

The comparative study of 4 Benzamides effects on the oestrus cycle of female rats has been done. These compounds were administered once daily for 21 consecutive days (1; 0,1; and 0,001 mg.kg-1.SC) on Wistar AF SPF rats smears. Our data show that sulpiride and sultopride suppress oestrus cycle substituted by a permanent dioestrus, while metoclopramide only extend the duration of the cycle and tiapride does not influence oestrus cycle.

Amisulpride↗
PubMedDate not supplied

5-HT1A and D-2 receptor affinity of o-methoxyphenylpiperazine derivatives with terminal benzamide fragment on N-4 alkyl chain. 2.

The synthesis of some o-methoxyphenylpiperazines with a benzamide moiety on N-4 alkyl chain was accomplished and their affinity for dopamine and serotonin receptor subtypes was assayed by in vitro receptor binding. The results show that several derivatives had a good affinity both on D-2 and 5-HT1A receptors, the IC50s ranging from 10(-7) to 10(-8) M.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

An anti-inflammatory benzamide derivative inhibits the protein kinase C (PKC)-dependent pathway of ERK2 phosphorylation in murine macrophages.

We have previously described benzamide derivatives that inhibited tumor necrosis factor (TNF) production from activated macrophages (Mphi) probably by interacting with a protein kinase C (PKC)-dependent pathway. To investigate their mode of action further, we first tested their effect on isolated PKC in vitro, using the selective inhibitor bisindolylmaleimide (BIM) as a positive control. We found that our representative compound JM34 did not inhibit PKC activity in vitro. We then investigated pathways located downstream of PKC and focused on the Raf1/MEK1,2/Erk1,2 cascade known to be preferentially activated by PKC activators such as phorbol esters. We found that JM34 dose-dependently inhibited Erk2 phosphorylation in Mphi stimulated by phorbol dibutyrate and calcium ionophore (maximal inhibition of 85% at 300 microM). BIM at 3 microM totally abrogated Erk2 phosphorylation. After stimulation with endotoxin or zymosan, Erk2 phosphorylation was only partially inhibited (25-30%) by JM34 or BIM, which confirmed that PKC-independent events were also involved in Erk2 phosphorylation. Because activated Erk2 has been shown to activate phospholipase A2, we tested the effect of JM34 and BIM on the release of arachidonate metabolites from activated Mphi. We found that both products partially inhibited the release of arachidonate metabolites from zymosan-activated Mphi at levels comparable to their inhibition of Erk2 phosphorylation. In contrast, JM34 and BIM markedly differed in their ability to inhibit TNF production. Taken together, our results suggest that JM34 inhibited the PKC-dependent pathway of Erk2 phosphorylation, which may fully account for its inhibitory effect on phospholipase A2 activation. However, the inhibition of TNF release by JM34 probably involved inhibition of an additional pathway, distinct from the Erk1/Erk2 cascade.

Animals↗
PubMed1990

[Antiestrogenic N-(4-hydroxyphenyl)-n-(1,1,1,-trifluoro-2-propyl)-4- hydroxybenzamides: influence of hydrophobic groups substituted in the ortho-position of the benzamide-fragment on activity].

Experiments are reported here to develop compounds with antiestrogenic and mammary tumor inhibiting properties. Analogues with hydrophobic groups in 2- or 2,6-position of the benzamide-fragment of N-(4-hydroxyphenyl)-N-(1,1,1-trifluoro-2-propyl)- 4-hydroxybenzamides were investigated. Compounds 2 and 3 proved to be "true" antiestrogenes among 2-7 (2: 2-CH3, 3: 2-F, 4: 2-Cl, 5: 2-Br, 6: 2,6-Cl2, 7: 2-CF3). Compound 4 showed the highest activity on the MXT-MC, ER+.

Animals↗
PubMed1993

Pharmacokinetics and metabolic interconversion of intravenous 4-amino-5-chloro-2-[(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl] benzamide and its sulfide and sulfone metabolites in rats.

The pharmacokinetics of a new 5-hydroxytryptamine (5HT3) receptor antagonist, 4-amino-5-chloro-2-[(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl] benzamide (ML-1035, 1), and its sulfone and sulfide metabolites were examined in 12 rats. Each of these compounds (25.4 mumol/kg) was administered to rats intravenously. Their plasma concentrations were measured by high-performance liquid chromatography. These plasma data revealed that 1, a sulfoxide, underwent interconversion with its sulfide metabolite. However, no interconversion was observed between 1 and its sulfone metabolite. Examination of mean times and additional properties of the 1/sulfide metabolite system revealed that total exposure times of 1 and the sulfide metabolite were moderately and weakly, respectively, influenced by the metabolic interconversion process. However, the tissue distribution process strongly influenced the total exposure times of both compounds. The disposition of the sulfone metabolite of 1 was also strongly influenced by the tissue distribution process. In addition, < 3% of the intravenous dose of 1 or the sulfide was available to the general circulation as the sulfone metabolite.

Animals↗
PubMed1994

Determination of bioavailability and systemically available fractions of drugs undergoing reversible metabolism: application to 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2- (diethylamino)ethyl]benzamide and its sulfide and sulfone metabolites in rats.

Methods are discussed which permit the calculation of the bioavailability (F) and fraction of an oral dose entering the central circulation (f) of a drug and its interconversion metabolite. The interrelationships between the F and f and between the F and systemically available fractions afforded by reversible metabolism are also derived and described. The application of these principles is illustrated by the pharmacokinetic analysis of 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2- (diethylamino)ethyl]benzamide (ML-1035, 1) and its sulfide (2) and sulfone (3) metabolites in rats. Like intravenous ML-1035, ML-1035 administered orally underwent metabolic interconversion with 2 but not with 3 in this species. Both ML-1035 and 2 were absorbed rapidly and are pharmacologically active. On average, 8.3 and 13% of an oral dose (152.4 mumol/kg) of ML-1035 were bioavailable as ML-1035 and its sulfide metabolite, respectively, while 23 and 65% of a molar equivalent dose of the sulfide metabolite were bioavailable as either compound, respectively. Thus, the sulfide metabolite is better absorbed than ML-1035 in rats. Following oral administration of either ML-1035 or 2, the systemically available fractions of both compounds were weakly to moderately influenced by the reversible metabolism process in rats. Moreover, the bioavailability of the sulfone metabolite was very poor (2.5-4%) following separate oral administration of ML-1035, 2, and 3.

Animals↗
PubMed1995

Nonselective and efficient fluorescent labeling of glycans using 2-amino benzamide and anthranilic acid.

Reaction conditions for conjugation of two fluorescent ortho-substituted aniline derivatives, 2-amino benzamide (2-AB) and 2-anthranilic acid (2-AA), to N- and O-glycans have been investigated. Conjugation conditions for attaching 2-AB and 2-AA to core-fucosylated and non-fucosylated glycans were developed using complex N-glycans radiolabeled at the nonreducing terminus with [3H]C6-galactose. Optimal conditions for each of the following reaction parameters were experimentally defined: [glycans], [2-AB] or [2-AA], solvent and acid composition, temperature and time of Schiff's base formation, nature of reductant, and temperature and time of reduction. Using the optimized reaction conditions it has been shown with several standard glycans and glycoprotein-derived glycan libraries that (i) molar labeling efficiencies are high and essentially independent of the amount of glycans; (ii) negligible (< 2 mol%) desialylation occurs during conjugation; (iii) glycan labeling is nonselective, i.e., independent of glycan structure; and (iv) insignificant fluorescent or chemical "blank" is recovered during the glycan-labeling and purification protocol. Labeling glycan pools with 2-AB or 2-AA therefore allows representative glycan profiles to be obtained and also allows relative molar quantitation of individual glycans in a pool. The 2-AB label is compatible with several chromatographic means for separation of carbohydrates including Bio Gel P4 gel permeation, high-performance anion-exchange chromatography with fluorescence detection, and a variety of HPLC procedures, as well as with mass spectrometric methods including matrix-assisted laser desorption-mass spectrometry and electrospray-mass spectrometry. The 2-AA label is particularly well-suited for electrophoretic separations by polyacrylamide gel electrophoresis. These fluorophores show high intrinsic sensitivity and thus facilitate very sensitive analysis of protein glycosylation.

Chromatography, High Pressure Liquid↗
PubMed2006

The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells.

Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder causing infant death in half of all patients. Homozygous loss of the survival motor neuron 1 (SMN1) gene causes SMA, whereas the number of the SMN2 copy genes modulates the severity of the disease. Due to a silent mutation within an exonic splicing enhancer, SMN2 mainly produces alternatively spliced transcripts lacking exon 7 and only approximately 10% of a full-length protein identical to SMN1. However, SMN2 represents a promising target for an SMA therapy. The correct splicing of SMN2 can be efficiently restored by over-expression of the splicing factor Htra2-beta1 as well as by exogenous factors like drugs that inhibit histone deacetylases (HDACs). Here we show that the novel benzamide M344, an HDAC inhibitor, up-regulates SMN2 protein expression in fibroblast cells derived from SMA patients up to 7-fold after 64 h of treatment. Moreover, M344 significantly raises the total number of gems/nucleus as well as the number of nuclei that contain gems. This is the strongest in vitro effect of a drug on the SMN protein level reported so far. The reversion of Delta7-SMN2 into FL-SMN2 transcripts as demonstrated by quantitative RT-PCR is most likely facilitated by elevated levels of Htra2-beta1. Investigations of the cytotoxicity of M344 using an MTT assay revealed toxic cell effects only at very high concentrations. In conclusion, M344 can be considered as highly potent HDAC inhibitor which is active at low doses and therefore represents a promising candidate for a causal therapy of SMA.

Alternative Splicing↗
PubMed1984

Pharmacokinetic study of digoxin-benzamide interaction in the rat.

Simultaneous oral administration of digoxin and three benzamides (Metoclopramide, Alizapride, Bromopride) to the rat, modify digoxin's pharmacokinetic parameters: peak plasma concentration, elimination phase half life and bioavailability (Bromopride, Alizapride in function with dose-level). Our conclusion, is that drug-monitoring is necessary for this drug association.

Administration, Oral↗
PubMed1983

Inhibition in carotid body chemoreceptors mediated by D-2 dopaminoceptors: antagonism by benzamides.

Inhibition of chemosensory nerve impulses in the cat is evoked by dopamine (DA) applied to carotid body chemoreceptors. Pharmacological characterization of the dopaminoceptors involved in this action was determined through their blockade with benzamides, selective antagonists of D-2 receptors. Both metoclopramide and sulpiride were effective blockers of DA-induced chemosensory inhibition. Furthermore, both drugs induced an immediate increase in the frequency of carotid nerve chemosensory impulses, suggesting the presence of previous tonic inhibition of chemoreceptor discharges by endogenous DA released from glomus cells.

Animals↗