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At least 19 recordsLinked to original sources
PubMed1987

Benzamide-DNA interactions: deductions from binding, enzyme kinetics and from X-ray structural analysis of a 9-ethyladenine-benzamide adduct.

The interaction of benzamide with the isolated components of calf thymus poly(ADP-ribose) polymerase and with liver nuclei has been investigated. A benzamide-agarose affinity gel matrix was prepared by coupling o-aminobenzoic acid with Affi-Gel 10, followed by amidation. The benzamide-agarose matrix bound the DNA that is coenzymic with poly(ADP-ribose) polymerase; the matrix, however, did not bind the purified poly(ADP-ribose) polymerase protein. A highly radioactive derivative of benzamide, the 125I-labelled adduct of o-aminobenzamide and the Bolton-Hunter reagent, was prepared and its binding to liver nuclear DNA, calf thymus DNA and specific coenzymic DNA of poly(ADP-ribose) polymerase was compared. The binding of labelled benzamide to coenzymic DNA was several-fold higher than its binding to unfractionated calf thymus DNA. A DNA-related enzyme inhibitory site of benzamide was demonstrated in a reconstructed poly(ADP-ribose) polymerase system, made up from purified enzyme protein and varying concentrations of a synthetic octadeoxynucleotide that serves as coenzyme. As a model for benzamide binding to DNA, a crystalline complex of 9-ethyladenine and benzamide was prepared and its X-ray crystallographic structure was determined; this indicated a specific hydrogen bond between an amide hydrogen atom and N-3 of adenine. The benzamide also formed a hydrogen bond to another benzamide molecule. The aromatic ring of benzamide does not intercalate between ethyladenine molecules, but lies nearly perpendicular to the planes of stacking ethyladenine molecules in a manner reminiscent of the binding of ethidium bromide to polynucleotides. Thus we have identified DNA as a site of binding of benzamide; this binding is critically dependent on the nature of the DNA and is high for coenzymic DNA that is isolated with the purified enzyme as a tightly associated species. A possible model for such binding has been suggested from the structural analysis of a benzamide-ethyladenine complex.

Adenine↗
PubMed1981

Synthesis and neuroleptic activity of benzamides. Cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide and related compounds.

Three series of benzamides of N,N-disubstituted ethylenediamines (linear alkane-1,2-diamines), 1-substituted 2-(aminomethyl)pyrrolidines, and 1-substituted 3-aminopyrrolidines (cyclic alkane-1,2-diamines) were designed and synthesized as potential neuroleptics. All target compounds were evaluated for their inhibitory effects on apomorphine-induced stereotyped behavior in rats, and a good correlation between structure and activity was found throughout the series. In the linear series (analogues of metoclopramide), introduction of a benzyl group on the terminal nitrogen, rather than an ethyl group, and a methyl group on the p-amino group of metoclopramide both enhanced the activity. The resulting N-[2-(N-benzyl-N-methylamino)ethyl]-5-chloro-2-methoxy-4-(methylamino) benzamide(23) was about 15 times more active than metoclopramide. In the cyclic series, particularly among the benzamides of 1-benzyl-3-aminopyrrolidine, most of the compounds tested were more active than the corresponding linear benzamides. cis-N-(1-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino) benzamide (YM-09151-2, 55) was the most active among all of the compounds tested, being 13 and 408 times more potent than haloperidol and metoclopramide, respectively. Moreover, compound 55 exhibited a fairly high ratio of antistereotypic activity to cataleptogenicity compared with haloperidol and metoclopramide. It is expected that compound 55 may be used as a potent drug with few side effects in the treatment of psychosis.

Animals↗
PubMed1999

Design, anticonvulsive and neurotoxic properties of retrobenzamides. N-(Nitrophenyl)benzamides and N-(aminophenyl)benzamides.

Design, anticonvulsant properties in maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N-(nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values--including the dose offering anticonvulsant protection in 50% of tested animals (ED50) and protective indices--obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test.

Administration, Oral↗
PubMed1992

Novel benzamides as selective and potent gastrokinetic agents. III. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]-benzamides.

A series of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]benzamides (11-64) were prepared and evaluated for gastrokinetic activity by determining their effects on the gastric emptying of phenol red semisolid meal in rats. The N-4 substituent includes alkyl, phenoxyalkyl, (4-fluorobenzoyl)alkyl, and heteroarylmethyl groups. The benzamide derivatives, having an isopropyl, isoamyl, neopentyl, 3-(4-chlorophenoxy)-propyl, or pyridylmethyl group at N-4, showed potent in vivo gastric emptying activity. In particular, 4-amino-5-chloro-2-ethoxy-N-[[4-(3-pyridylmethyl)-2- morpholinyl]methyl]benzamide (57b) was equipotent to the 4-fluorobenzyl analogue 1b (AS-4370 as its citrate) in the gastrokinetic activity on phenol red semisolid meal in rats and mice, and on resin pellet solid meal in rats. Moreover, compound 57b was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests. Structure-activity relationships of compounds with various substituents at N-4 are also discussed.

Animals↗
PubMedDate not supplied

[Rational conception, synthesis and evaluation of phenytoinergic potential anticonvulsants. A series ofretrobenzamides: N-(nitrophenyl) benzamides and N-(aminophenyl) benzamides].

Retrobenzamides [N-(nitrophenyl) benzamides and N-(aminophenyl)benzamides] were developed in the perpective of a design for phenytoinergic agents. Anticonvulsant and neurotoxic properties of these compounds were evaluated in mice and rats in two seizure models (maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentylenetetrazole [scPtz]) and in the rotorod test. Data obtained were compared with those recorded on carbamazepine and phenytoin (antiepileptic drugs widely utilized in human clinics), ameltolide (anticonvulsant compound recently developed by Eli Lilly in human clinical trials) and other compounds previously reported by our research group. Studies on retrobenzamides in mice administered by intraperitoneal route point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity in the case of the corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were less active in the MES test than in mice dosed intraperitoneally.

Animals↗
PubMed1980

Specific activation of puff 93D of Drosophila melanogaster by benzamide and the effect of benzamide treatment on the heat shock induced puffing activity.

A 10 or 20 min in vitro treatment of salivary glands of late 3rd instar larvae of Drosophila melanogaster with 1 mg/ml benzamide (BM) at 24 degrees C results in the specific induction of the 93D puff and at the same time all other chromosomal RNA synthesis is severely repressed. Incorporation of 3H-uridine in the nucleolus is not affected. In glands heat shocked (37 degrees C) for 20 min in presence of BM, all the temperature shock (TS) puffs are induced but they incorporate 3H-uridine to a lesser extent than in glands heat shocked in absence of BM. The 93D puff, which is highly induced by either of the treatments alone, is relatively less active in glands exposed to TS and BM simultaneously. When a 10 min BM treatment (at 24 degrees C) incorporation on all TS puffs is relatively less and significantly, in both cases, the 87C puff is much less active active (more so in TS followed by BM treated glands) than the 87A puff. Also, in both these treatments, the 93D puff does not show ant additive effect on the BM and TS treatments. These observations are discussed in the light of possible role of the 93D puff in modulating the heat shock response.

Animals↗
PubMed1991

Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.

The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.

Animals↗
PubMed1990

Novel benzamides as selective and potent gastric prokinetic agents. 1. Synthesis and structure-activity relationships of N-[(2-morpholinyl)alkyl]benzamides.

With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity.

Animals↗
PubMed1988

Liquid chromatographic determination of serum levels of d,l-4-amino-N-(alpha-methylbenzyl)-benzamide, a new benzamide anticonvulsant.

A method for the high-performance liquid chromatographic (HPLC) determination of serum concentrations of d,l-4-amino-N-(alpha-methylbenzyl)-benzamide and its N-acetylated metabolite is described. The compounds are isolated from a 50-microL sample of serum using solid phase extraction. The compounds and internal standard are eluted from the extraction column with acetonitrile. Quantitation is performed via UV detection at 275 nm following isocratic reversed-phase (C18) separation using a ternary solvent system. The assay procedure is useful for the determination of concentrations of parent compound from 0.63 to 87.9 micrograms/mL from 50 microL of serum.

Acetylation↗
PubMed1992

Sex-differences in the disposition of substituted benzamides: pharmacokinetics of a gastroprokinetic agent (4-amino-5-chloro-2-[2- (methylsulfinyl) ethoxy]-N-[2-(diethylamino)ethyl] benzamide hydrochloride) (ML-1035) in male and female New Zealand white rabbits.

The disposition of 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N- [2-(diethylamino)ethyl] benzamide hydrochloride (ML-1035) following intravenous (10 mg kg-1) and oral (200 mg kg-1) dosing was investigated in male and female New Zealand white rabbits. After intravenous dosing ML-1035 was eliminated with a half-life of 1.45 +/- 0.49 h in males and 0.79 +/- 0.08 h in females. Volume of distribution at steady-state was 2.08 +/- 0.98 l kg-1 in males and 9.11 +/- 5.86 l kg-1 in females. Clearance averaged 2.99 +/- 1.11 l h-1 kg-1 in males and 16.73 +/- 7.29 l h-1 kg-1 in females. All pharmacokinetic parameters were significantly different between males and females (p < 0.05). Absolute bioavailability after oral administration was 7.35 per cent for males and 12.31 per cent for females, suggesting that ML-1035 undergoes significant first-pass elimination. Plasma area under the curve for the metabolites of ML-1035 after both oral and intravenous administration were also different between the two sexes. These data suggest that the disposition of ML-1035 shows significant differences between male and female rabbits.

Administration, Oral↗
PubMed2002

Benzamide riboside, a recent inhibitor of inosine 5'-monophosphate dehydrogenase induces transferrin receptors in cancer cells.

Benzamide riboside, a recently discovered inhibitor of IMP dehydrogenase (IMPDH) exhibits oncolytic activity. IMPDH is the key enzyme of de novo guanylate biosynthesis and was shown to be linked with proliferation. Therefore, IMPDH is a very good target for antitumor therapy. In order to be active, benzamide riboside has to be converted to BAD, an NAD analogue that binds to the NAD site on IMPDH. Inhibition of the enzyme by benzamide riboside selectively inhibits tumor cell growth and induces apoptosis in various human tumor cell lines. In this manuscript we describe the induction of the CD71 transferrin receptor in human promyelocytic leukemia HL-60 cells following treatment with benzamide riboside. The results indicate a possible involvement of the iron metabolism in the action of this new compound. Benzamide riboside might be clinically used in the treatment of leukemia and solid tumors, alone or as part of combination therapy. Since transferrin receptors are overexpressed in certain cancers, such as glioma and colon cancer, a combination therapy that includes benzamide riboside in transferrin-coupled liposomes will not only target cancer cells but also leads to suicidal action because benzamide riboside will upregulate transferrin receptors on cancer cells thereby make it accessible to dose-intensive chemotherapy. We therefore believe that benzamide riboside itself or derivatives of benzamide riboside might become an important addition for the treatment to diseases that are otherwise fatal.

Antigens, CD↗
PubMed1983

Effects of a series of substituted benzamides on rat prolactin secretion and 3H-spiperone binding to bovine anterior pituitary membranes.

The potency of seven substituted benzamide drugs (AHR-5531B, AHR-5645B, AHR-6092, AHR-8764, bromopride, sultopride and tiapride) to stimulate rat prolactin (PRL) secretion in vivo was found to be three orders of magnitude greater than that of non-benzamide neuroleptic drugs relative to their respective abilities to inhibit 3H-spiperone binding to bovine anterior pituitary membranes. Nevertheless, the IC50 values for the inhibition of 3H-spiperone binding by the seven substituted benzamide drugs was significantly correlated with their high potency to stimulate rat PRL secretion in vivo. Further, the slope of the regression line for these substituted benzamides paralleled that of a series of butyrophenone, phenothiazine, morphanthridine and dibenzodiazepine neuroleptic drugs. Two benzamide (sulpiride and metoclopramide) and three non-benzamide neuroleptic drugs gave intermediate results. This data suggests that blockade of different subgroups of dopamine receptors in the anterior pituitary gland labeled by 3H-spiperone may be responsible for the in vivo stimulation of PRL secretion by the benzamide and non-benzamide neuroleptic drugs.

Animals↗
PubMed1989

Benzamide prevention of ultraviolet radiation-induced transformation as measured by anchorage-independent growth and the absence of correlation with thymidine dimer formation and DNA repair.

Synchronized human fibroblasts were exposed in early S phase to increasing doses of ultraviolet (UV) irradiation in the presence and absence of an antitransforming drug, benzamide. Cellular survival, initial thymidine dimer formation and its repair, and cellular phenotypic transformation were simultaneously monitored in the presence and absence of 1 mM externally added benzamide that reaches 8 to 15 microM intracellular levels. Cellular transformation as measured by an expression of anchorage-independent growth was inhibited by nontoxic doses of benzamide. Antitransforming action of benzamide is confined to low intracellular drug concentrations, which in the case of benzamide is in the 4-9 microM range. Because of the lack of effect of benzamide on the formation of UV-induced thymidine dimers and the specific repair of these dimers, these results suggest that the processes of thymidine dimer formation and its repair are not involved in the mode of action of benzamide that influences the expression of a transformed phenotype with low malignant vigor.

Benzamides↗
PubMed1996

Benzamide, an inhibitor of poly(ADP-ribose) polymerase, attenuates methamphetamine-induced dopamine neurotoxicity in the C57B1/6N mouse.

Previous studies have indicated that the activation of poly(ADP-ribose) polymerase (PARP), an enzyme involved in DNA plasticity-related phenomena, is an early event occurring in glutamate-induced neurotoxicity in vitro, and that inhibitors of PARP, including benzamide, are protective against both glutamate- and methamphetamine (METH)-induced neurotoxicity in vitro. To evaluate a central neuroprotective potential of benzamide in vivo, the present study examined the effect of benzamide on the nigrostriatal dopamine toxicity (i.e., long-lasting striatal dopamine depletion) induced by METH in the C57B1/6N mouse. Intraperitoneal injection of METH at 2-h intervals (4 injections of 5 mg/kg, 4 injections of 10 mg/kg, or 2 injections of 20 mg/kg) dose-dependently reduced the levels of striatal dopamine in male C57B1/6N mice by up to 53% at 7 days post-treatment. Administration of benzamide (2 injections of 160 mg/kg spaced by a 4 interval) during the different METH treatment protocols partially and significantly attenuated the METH-induced dopamine depletions. Benzamide (160 mg/kg i.p.) by itself had no acute effect on striatal dopamine metabolism and did not reduce body temperature. The concentrations of benzamide measured in the striatum at different times following this same dose of drug were in a range (0.09-0.64 mM) reported in in vitro studies to be both neuroprotective and effective in inhibiting PARP activity. These results indicate a neuroprotective potential of benzamide in vivo and suggest a role of PARP in METH neurotoxicity.

Animals↗
PubMed2005

Benzamide and 4-amino 1,8 naphthalimide treatment inhibit telomerase activity by down-regulating the expression of telomerase associated protein and inhibiting the poly(ADP-ribosyl)ation of telomerase reverse transcriptase in cultured cells.

To test the role of poly(ADP-ribose) polymerase on the telomerase activity, we determined the telomerase activity in leukemic cells K562 treated with benzamide and 4-amino 1,8 naphthalimide (NAP), the inhibitors of PARP. We observed that both the agents inhibited telomerase activity in a dose-dependent manner. The doses of benzamide and NAP that inhibited telomerase activity to 50% of untreated control cells were 10.7 +/- 0.6 mm and 200 +/- 7 microm, respectively. Benzamide treatment (10 mm) inhibited telomerase activity in a time-dependent manner. We also tested the ability of benzamide to inhibit the telomerase activity in Chinese hamster V79 cells and observed similar inhibition of the telomerase activity. Expression of telomerase reverse transcriptase (TERT) and telomerase RNA component, detected by RT-PCR, remained unaltered by treatment with benzamide or NAP. On the contrary, the expression of telomerase associated protein (TEP1/TP1), as detected by RT-PCR and western blot analysis, was reduced by both the agents. Further, in K562 cells, immunoprecipitation with the anti-TERT IgG and probed anti-poly (ADP-ribose) IgG revealed that TERT was poly(ADP-ribosyl)ated in the physiological condition of cell growth and such poly(ADP-ribosyl)ation was inhibited by benzamide treatment. Decrease in TEP1/TP1 expression and poly(ADP-ribosyl)ation of TERT were correlated with the inhibition of PARP activity by benzamide, indicating that PARP had a role in telomerase activity through poly(ADP-ribosyl)ation of TERT and down-regulation of TEP1/TP1.

1-Naphthylamine↗
PubMed1997

The human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein zinc ejection activity of disulfide benzamides and benzisothiazolones: correlation with anti-HIV and virucidal activities.

It has been shown previously by our group and others that a series of four disulfide benzamides with cellular anti-human immunodeficiency virus (HIV) activity can eject zinc from HIV type 1 nucleocapsid protein (NCp7) in vitro while analogs without antiviral activity do not. We also found that the zinc ejection activity correlates with the loss of the ability of NCp7 to bind to HIV psi RNA in vitro. These observations indicate that the antiviral disulfide benzamides may act at a novel retroviral target of action, i.e., the nucleocapsid protein. The present studies examine the relationship among disulfide benzamide structure, in vitro NCp7 zinc ejection activity, and antiviral activity for a larger series of compounds. All of the antiviral disulfide benzamides were found to eject NCp7 zinc, while some disulfide benzamides with zinc ejection activity are not antiviral. Utilizing the thiol reagent 5,5'-dithiobis(2-nitrobenzoic acid), it was determined that the o-amido-phenyl disulfides being studied cyclize in aqueous solution to form benzisothiazolones. A series of benzisothiazolones, which are stable in solution in the absence of dithiothreitol, were found to eject NCp7 zinc at a rate similar to that of their disulfide benzamide analogs and to possess similar antiviral activity. It was also found that the relative rates of HIV inactivation by various disulfide benzamides and benzisothiazolones correlate with their relative kinetic rates of NCp7 zinc ejection, which is consistent with the nucleocapsid protein being the target of action of these compounds.

Anti-HIV Agents↗