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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↗
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↗
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↗
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↗
PubMed1985

Benzamide on chondrocytic differentiation in chick limb bud cell culture.

Benzamide, an inhibitor of (ADP-ribose) transferase, augmented chondrocytic differentiation of chick limb bud mesenchymal cells in micromass cultures; the incorporation of 35SO4(2-) into the trichloroacetic-acid-insoluble constituents of cell masses as well as the formation of cartilage nodules (Nishio, Nakanishi, Doull & Uyeki, 1983) occurred about 24 h earlier than in untreated cultures and continued to be enhanced in benzamide-treated cultures of stage 23- to 24-chick limb bud cells. Benzamide also significantly increased cell proliferation. However, benzamide did not affect DNA and RNA syntheses except for one period: 24 to 30 h after the start of culture, RNA synthesis was stimulated. From 48 h of culture, (ADP-ribose) transferase activity decreased daily in untreated cultures, whereas benzamide treatment diminished (ADP-ribose) transferase activity 24 h earlier. On the other hand, intracellular NAD levels increased daily in untreated cultures, and benzamide significantly increased the NAD levels above untreated cultures. ATP levels did not differ significantly during the culture period, and benzamide did not affect ATP levels.

Adenosine Triphosphate↗
PubMed1991

Prokinetic benzamides stimulate peristaltic activity in the isolated guinea pig ileum by activation of 5-HT4 receptors.

Substituted benzamides such as metoclopramide, cisapride, zacopride, renzapride or BRL 20627, stimulate intestinal motility in various species. As they are antagonists at 5-HT3 and agonists at 5-HT4 receptors and as both mechanisms could potentially contribute to their gastrointestinal prokinetic effect, the underlying mechanism is unclear. To clarify this, the effect of some substituted benzamides on gut motility was investigated in the isolated guinea pig ileum using the Trendelenburg technique, in which pressure-induced peristaltic contractions are measured. All benzamides stimulated the peristaltic reflex with the rank order of potency: renzapride greater than cisapride greater than BRL 20627 greater than (+/-)-zacopride greater than metoclopramide. ICS 205-930, granisetron and 2-methyl-5-HT did not change the peristaltic response. 5-HT and 5-methoxytryptamine potently mimicked the effect of the benzamides. The effect of 5-HT was not blocked by ICS 205-930 (10(-7) M). These results indicate that the Trendelenburg preparation is suitable for the investigation of intestinal prokinetic effects of the substituted benzamides. Furthermore, the results suggest that the intestinal effect of benzamides results from activation of 5-HT4 receptors rather than from blockade of 5-HT3 receptors.

Animals↗
PubMed1990

Potential antipsychotic agents. 7. Synthesis and antidopaminergic properties of the atypical highly potent (S)-5-bromo-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide and related compounds. A comparative study.

(S)-5-Bromo-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide (6) and some related compounds, i.e. the R isomer 7, the 3-hydroxy analogue 8, the desbromo derivative 9, the monomethoxy compound 10, and the 2,4-dimethoxy analogue 11, have been synthesized from the corresponding benzoic acids. The benzamides, lacking o-hydroxy groups, were evaluated for their affinity for the [3H]spiperone binding site and for their inhibition of apomorphine-induced behavioral responses in relation to the effect of the corresponding salicylamides. Besides the 2-hydroxy-3-methoxybenzamide 12 and the related 1,4-benzodioxane (13) and 2,3-dihydrobenzofuran (14), carboxamides were investigated in order to evaluate the stereoelectronic requirements on the 2-methoxy group for the receptor interaction. The study supports the view that the o-methoxy group may adopt coplanar, as well as perpendicular orientations, and maintain the intramolecular hydrogen bonding required in the bioactive conformation. The benzamide 6 was found to be equipotent with the analogous highly active salicylamide 3 (FLB 463) both in vitro and in vivo. In addition, 6 displayed a preferential inhibition of the hyperactivity component of the behavioral syndrome, which is regarded to indicate a low tendency to induce extrapyramidal side effects in man at antipsychotically effective doses. The benzamide class of compounds (6-10) were found to be somewhat more sensitive to the structural modifications than the salicylamide class, i.e. the o-hydroxy-substituted benzamides (2-5). The potent and selective benzamide 6 (FLB 457) is highly suitable for investigations of dopamine D-2 mediated responses and, in radiolabeled form, for receptor binding studies in vitro and in vivo.

Animals↗
PubMed1987

2-Phenylpyrroles as conformationally restricted benzamide analogues. A new class of potential antipsychotics. 1.

2-Phenylpyrroles were synthesized as conformationally restricted analogues of the substituted benzamide sultopride and the butyrophenones haloperidol and fluanisone. Dopamine antagonistic activity is maintained if the 2-phenylpyrrole side chain is linked to the pharmacophoric N-ethylpyrrolidine moiety of sultopride or to the 4-substituted piperazine moiety of fluanisone but is lost if the 2-phenylpyrrole is combined with the 4-substituted piperidine moiety of haloperidol. The 2-phenylpyrrole analogue 1 of sultopride is in vitro 0.25 and in vivo 3 times as potent as the parent compound. Its binding to the dopamine D-2 receptors is, in analogy to the substituted benzamides, strongly sodium-dependent. The 2-(4-fluorophenyl)pyrrole analogue 5 of fluanisone is superior in vitro as well as in vivo to the corresponding benzamide 7 and the butyrophenone fluanisone. The increase in activity is not only due to a higher affinity for the D-2 receptors but also to an enhanced oral absorption (ratio po/ip = 4.5 vs 40 for the benzamide and 60 for fluanisone). Compound 5 is further characterized by a high selectivity for the D-2 receptors, in contrast to the benzamide and butyrophenone analogues (ratio D-2/alpha 1 = 60, 2.0, and 0.3, respectively). The binding to the D-2 receptors has little dependence on sodium. The 2-phenylpyrrole 5 shares with the benzamide 7 a low potential to induce catalepsy, which is in contrast to haloperidol. So, 5-(4-fluorophenyl)-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]pyrrole (5) is the prototype of a new class of sodium-independent dopamine D-2 antagonists, which may be particularly useful as potential antipsychotics with a low propensity to induce acute extrapyramidal side effects.

Animals↗
PubMed1989

The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons.

We have previusly shown that a non-classical 5-hydroxytryptamine (5-HT4) receptor mediates the stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture. The pharmacological characteristics of this receptor exclude the possibility that it belongs to the known 5-HT1, 5-HT2 or 5-HT3 receptor types. Here we report that this 5-HT receptor can be stimulated by 4-amino-5-chloro-2-methoxy substituted benzamide derivatives. All these compounds have been reported to be potent stimulants of gastrointestinal motility and some of them are 5-HT3 receptor antagonists. The rank order of potency of these substituted benzamide derivatives in stimulating cAMP formation was: cisapride greater than BRL 24924 greater than 5-HT greater than zacopride greater than BRL 20627 greater than metoclopramide. The non-additivity of benzamide and 5-HT activities suggests that 5-HT and the substituted benzamide derivatives act on the same receptor. Only ICS 205930, a recognized 5-HT3 receptor antagonist, competitively antagonized the stimulatory effect of cisapride, zacopride and BRL 24924. However, its pKi (6-6.3) for this new receptor was very different from its pKi for 5-HT3 receptors (pKi = 8-10). Other selective 5-HT3 receptor antagonists with an indole group (BRL 43694 and GR 38032F), with a benzoate group (cocaïne, MDL 72222) or with a piperazine group (quipazine) were ineffective in reversing the stimulatory effect of benzamide derivatives. Exposure of neuronal cells to potent agonists at this receptor such as BRL 24924 rapidly reduces its capacity to stimulate cAMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1992

Conformational analysis of dopamine D-2 receptor antagonists of the benzamide series in relation to a recently proposed D-2 receptor-interaction model.

Conformational analysis using molecular mechanics calculations (MM2(87)) has been performed for four different types of benzamides which display high affinity for the dopamine D-2 receptor. In order to elucidate the conformation of the receptor-bound molecules, a previously described dopamine D-2 receptor-interaction model has been employed. We conclude that all four types of benzamides accommodated in the proposed receptor-interaction model are in low-energy conformations. An acyclic amide side chain is concluded to adopt an extended conformation in the receptor-bound benzamide. A phenylpyrrole analogue of the benzamides could similarly be fitted to the model. Using the receptor-interaction model, the enantioselectivity of benzamides with an N-ethyl-2-pyrrolidinylmethyl side chain could be rationalized in terms of different conformational energies of the receptor-bound enantiomers. Two different receptor sites for N-alkyl substituents are suggested.

Benzamides↗
PubMed1991

Analysis of serotonergic mechanisms underlying benzamide-induced gastroprokinesis.

Serotonin (5-HT) receptors in the myenteric plexus mediate contractility in vitro and may regulate gastric emptying in vivo. This report examines the pharmacology of three benzamides, ML-1035 (4-amino-5-chloro-2-[2-(methylsulfinyl)-ethoxy]-N-[2- (diethylamino)ethyl]-benzamide hydrochloride), metoclopramide and cisapride, in studies which address the serotonergic mechanisms underlying benzamide-induced gastroprokinesis. All three compounds had high affinity at the 5-HT3 receptor as they displaced the 5-HT3 antagonist [3H]GR65630 from cortical membranes (Ki = 156, 232 and 1711 nM for ML-1035, metoclopramide and cisapride, respectively) and blocked the 5-HT-induced Bezold-Jarisch reflex, although cisapride was much less active in this experiment. Receptor selectivity was also compared at 5-HT1, 5-HT2, and dopamine D2 receptors in which no displacement was observed that was common to all agents. All benzamides elicited a 5-HT4-like agonist response as they enhanced field-stimulated neurogenic contractions in ileum (EC50 = 1.4, 1.6 and 0.013 microM for ML-1035, metoclopramide and cisapride, respectively). ICS 205-930, a proposed 5-HT4 antagonist, competitively antagonized this response for ML-1035 (Kb = 1.6 microM) whereas atropine blocked the twitch response and any additional responses to ML-1035. In vivo, ML-1035 and metoclopramide increased gastric emptying (IC50 = 0.87 and 3.09 mg/kg i.p., respectively). Thus, the benzamides activate a 5-HT4 receptor in the ileum which increases cholinergic contractions and may be one mechanism by which these agents increase gastric emptying.

Animals↗
PubMed1987

Further evidence for a different mode of action of caffeine and benzamide on mammalian cells.

Post-treatment with 2 mM caffeine or 2 mM benzamide increased the lethality of MNNG (N-methyl-N'-nitro-N-nitrosoguanidine) treated V79 cells; in the presence of 50 microM deoxycytidine, the caffeine effect was eliminated whereas the benzamide effect remained the same. Combined treatment with caffeine/benzamide alone produced a large amount of cell lethality which was eliminated by 50 microM deoxycytidine. Benzamide produced a strong inhibition of the poly(ADP-ribose)polymerase activity present in cell-free extracts prepared from V79 cells with greater than 90% inhibition at 2 mM concentration; caffeine on the other hand did not produce any substantial inhibition of this activity in the 2-5 mM range. These results further substantiate our earlier hypothesis that the mode of action of caffeine and benzamide on eukaryotic cells containing DNA damage are not identical [S.K. Das, C.C. Lau and A.B. Pardee (1984) Mutation Res., 131, 71-79].

Animals↗
PubMed1991

Potential antipsychotic agents. 9. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class of substituted (R)-N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides. Relations to other side chain congeners.

A number of substituted N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides and -salicylamides have been prepared and investigated as dopamine D-2 receptor antagonists in vitro and in vivo. The affinity was found to be confined to the R enantiomer, in contrast to the corresponding N-ethyl or N-allyl derivatives. The X-ray structure of one of the compounds (15) confirmed the R stereochemistry. This compound (15) was found to adopt a solid-state conformation in which the 4-fluorobenzyl group is folded over the salicylamide moiety. Benzamides having a 2,3-dimethoxy substitution pattern (24 and 26) or salicylamides with a 5,6-dimethoxy grouping (21 and 22) were especially potent, in that they inhibited [3H]spiperone binding to rat striatal dopamine D-2 receptors in vitro with IC50 values of about 1 nM. The new compounds' ability to block apomorphine-induced stereotypies correlated with the affinity for the [3H]spiperone binding site. Higher dose levels were necessary to induce catalepsy than to block the apomorphine-induced responses. The influence of the aromatic substituents on the potency of substituted benzamides with three types of side chains, i.e. (R)-(1-benzyl-2-pyrrolidinyl)methyl, (S)-(1-ethyl-2-pyrrolidinyl)methyl and 1-benzyl-4-piperidinyl, was compared. The 3-bromo-5,6-dimethoxysalicylamide substitution pattern was found to be the most general since it gave very potent compounds in all series. The substituted (R)-N-[(1-(4-fluoro-benzyl)-2-pyrrolidinyl)methyl]benzamides (26) and -salicylamides (22) are suitable for development into 18F radioligands without altering the parent structure.

Animals↗
PubMed1988

Comparison of the in-vitro receptor selectivity of substituted benzamide drugs for brain neurotransmitter receptors.

The in-vitro selectivity of a group of substituted benzamide drugs for brain neurotransmitter receptors was determined to assess the most appropriate drugs for use in human PET studies. All substituted benzamide drugs studied inhibited [3H]haloperidol and [3H]spiperone binding to rat striatal membranes. The most potent compounds were YM 09151-2, clebopride and raclopride. However, these substances also interacted in differing degrees with alpha-1, alpha-2, beta-adrenergic, 5-HT-1, 5-HT-2, and opiate sites. Sulpiride, alizapride, SL 74205, TER 1546 and tiapride were specific for D-2 receptors, but these drugs were active only in the 10(-7)-10(-6) M range. Raclopride, amisulpiride and sultopride showed a 100-1000 differentiation between action on dopamine sites compared with other neurotransmitter receptors. No such selectivity was observed for clebopride or YM 09151-2. Specific substituted benzamides such as alizapride, may be appropriate in high concentrations for defining the interaction of PET ligands with brain dopamine receptors. More potent, but selective, drugs such as raclopride and amisulpiride, may be effective in low concentrations as ligands for labelling dopamine receptor sites. However, the ability of these various substituted benzamide drugs to penetrate into brain and in-vivo to identify dopamine receptors in all brain areas must be assessed.

Animals↗