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PubMed1985

Preferential binding of benzo[a]pyrene diol epoxide to the linker DNA of human foreskin fibroblasts in S phase in the presence of benzamide.

Addition of benzamide (BZ) at the onset of S phase inhibited expression of the neoplastic phenotype in human foreskin fibroblasts treated in vitro with (+/-)-7 alpha,8 beta-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P diol epoxide) in early S phase. Analysis of the specific B[a]P diol epoxide-DNA adducts revealed that ca. 65% of the total adducts in BZ and non-BZ carcinogen-treated cells was the B[a]P diol epoxide-deoxyguanine adduct. Limited micrococcal nuclease digestion of the early S phase nuclei from cells treated with B[a]P diol epoxide indicated that the carcinogen binds equally to linker and core DNA. However, when the cells were predominantly in S phase, in the presence of BZ, there was ca. three times more binding of B[a]P diol epoxide to the linker DNA compared to the core region. The confluent cells in G1 cell arrest treated only with B[a]P diol epoxide also bound the carcinogen preferentially to the linker region. These data indicate that pretreatment of the cells with BZ at the onset of S phase established a preferential binding pattern in the linker DNA similar to that observed in the cells treated with B[alpha]P diol epoxide in G1 arrest.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1986

Differential radiosensitization of human tumour cells by 3-aminobenzamide and benzamide: inhibitors of poly(ADP-ribosylation).

The effect of 3-aminobenzamide (3AB) and benzamide (BZ) (inhibitors of poly(ADP-ribose) synthetase) on radiosensitivity was investigated in normal human fibroblasts and three human cell lines established from tumours with varying degrees of clinical radiocurability. The human tumour cell lines selected were: Ewing's sarcoma, a bone tumour usually considered radiocurable with moderate radiation doses; lung adenocarcinoma, a tumour considered radiocurable with high doses of radiotherapy; and osteosarcoma, a very resistant tumour which is rarely controlled by standard doses of radiotherapy. Poly(ADP-ribose) synthetase inhibitors were added to cultures 2 h prior to irradiation and removed 24 h after. Inhibitors were used at doses producing little or no toxicity in cells. In the presence of these inhibitors, a differential radiosensitization was observed. Ewing's sarcoma cells and normal human fibroblasts were sensitized to an equal extent by either 8 mM 3AB or 4 mM BZ. However, no sensitization was observed at these concentrations in the lung adenocarcinoma cells or osteosarcoma cells. The degree of radiosensitization in vitro by 3AB and BZ correlates well with the clinical radiocurability of these tumours in vivo.

Benzamides↗
PubMed2005

Naravelia zeylanica [corrected] occurrence of primary benzamides in flowering plants.

Extract of Naravelia zeylanica (Ranunculaceae) yielded three simple benzamides, 3,4-methylenedioxybenzamide, 4-methoxybenzamide and 4-hydroxy-3-methoxybenzamide. These simple C6C1 metabolites have been encountered as natural products for the first time. The compounds were identified by direct comparison of their spectral (1H- and 13C-NMR) and chromatographic (GCMS) data with those of authentic samples. Authentic 4-hydroxy-3-methoxybenzamide was synthesized in one step by treatment of 4-hydroxy-3-methoxybenzonitrile with sodium perborate. Authentic 3,4-methylenedioxybenzamide was synthesized from the corresponding acid.

Benzamides↗
PubMed1992

Selective inhibition of the BPDE-I-induced modification of the replicating DNA of S-phase cells, by benzamide and 3-aminobenzamide.

Treatment of human skin fibroblasts in early S-phase with (+-)7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE-I) results in more extensive modification of early replicating DNA than parental DNA. We have investigated the effects of benzamide (BZ) and 3-aminobenzamide (3-ABZ), inhibitors of transformation, on the modification of parental and replicating DNA of cells in early S-phase by BPDE-I. Synchronized cells were exposed to 5-bromodeoxyuridine at S-phase entry and treated 3 h later with 0.114 microM BPDE-I for 30 min. The cells at the time of treatment represent a radiolabeling index of 40 +/- 5% of the total number of cells. The replicated DNA was isolated from the non-replicated parental DNA on a CsCl gradient. A 32P-postlabeling procedure was used to quantitate the carcinogen-DNA adducts. The level of modification per nucleotide residue of the early replicated DNA was 1.6-2.2 times higher compared to the level of modification of the parental DNA. Addition of BZ inhibited the BPDE-I modification of the replicated DNA by 27-53%. There was no significant effect on the parental DNA modification. The major adduct that was quantitatively suppressed in the early replicated DNA was BPDE-I-trans-N2-dG. The addition of 3-ABZ also inhibited the modification of the dG by approximately 50% without significantly inhibiting the BPDE-I-dG adducts in the parental DNA. The data suggest that BZ and 3-ABZ inhibit the modification of specific sites in the replicating DNA leading to inhibition of transformation.

Benzamides↗
PubMed1989

Liquid chromatographic studies on the aqueous solution conformation of substituted benzamide drug models.

The aqueous solution conformation of a series of model benzamides related to the orthopramide dopamine receptor antagonists is evaluated by reversed-phase liquid chromatography (LC). The structure-retention relationship studies demonstrate the existence of an intramolecular hydrogen bond formed in aqueous solution for these compounds. The six-membered pseudoring formed by the association of the amide N-H and the oxygen of the 2-methoxy group (N-H...O) produces enhanced reversed-phase retention (increased capacity factors, k') relative to the 3- and 4-isomers. Deletion of either the acceptor oxygen or the donor N-H results in decreased C18 retention of the 2-isomer relative to the 3- and 4-isomers. These structure-retention relationship studies reveal the value of reversed-phase LC methods for evaluation of the aqueous solution conformation of the orthopramide-type compounds. Further studies show that N-substituted 2-hydroxybenzamides are intramolecularly associated in aqueous solution through either N-H...O or O-H...O six-membered rings. The 6-methoxysalicylamides are believed to be stabilized through O-H to carbonyl oxygen bonding in addition to the N-H...O pseudoring. For the 2,6-dimethoxybenzamides, steric factors prevent methoxy-amide coplanarity, thus no intramolecular hydrogen bond is formed. The result is a dramatic decrease in retention for the 2,6-isomer relative to the other positional isomers. These studies suggest that remoxipride and related 2,6-dimethoxybenzamides cannot form the six-membered pseudoring believed to be topographically equivalent to the aromatic ring in dopamine.

Benzamides↗
PubMed1990

Liquid chromatographic studies on the aqueous solution conformation of substituted benzamides related to remoxipride.

A series of disubstituted benzamides related to the sterically hindered 2,6-dimethoxybenzamide drugs, such as remoxipride, are prepared. The structure-retention relationships for these compounds are studied on hydrocarbon stationary phases in various hydroorganic mobile phases. The 2,6-dimethoxybenzamide displays a very low capacity factor under these reversed-phase conditions, suggesting that steric crowding prevents the formation of an amide-methoxy N-H...O intramolecular hydrogen bond. The corresponding 2-hydroxy-6-methoxybenzamide shows a dramatic increase in affinity for the hydrocarbon stationary phase, which is characteristic of strong intramolecular hydrogen bonding in these compounds. These results suggest that the aromatic ring--carbonyl aqueous solution conformation is almost 90 degrees in amides like remoxipride and changes to coplanarity upon demethylation of one methoxy group.

Antipsychotic Agents↗
PubMed2002

In vitro anti-Helicobacter pylori activity of BAS-118, a new benzamide derivative.

The antibacterial activity of BAS-118, a new benzamide derivative, against Helicobacter pylori and other species of bacteria was investigated, as was the in vitro ability of the compound to induce drug resistance in H. pylori. The MICs of BAS-118 for 155 isolates of H. pylori, including 30 clarithromycin (CAM)-resistant isolates (MIC > or= 1.56 mg/L) and 25 metronidazole (MNDZ)-resistant isolates (MIC >or = 6.25 mg/L), and 29 reference strains of other genera were determined by an agar dilution method. The MIC(50), MIC(90) and MIC range of BAS-118 for 100 randomly selected isolates of H. pylori were or =8 mg/L. In summary, BAS-118 is a novel anti-H. pylori agent with a potent and selective antibacterial activity, which includes CAM- and MNDZ-resistant isolates. Furthermore, BAS-118 does not appear to induce drug resistance readily in vitro.

Anti-Bacterial Agents↗
PubMedDate not supplied

Pharmacology of LY201409, a potent benzamide anticonvulsant.

LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide], an effective anticonvulsant in several animal models, is rapidly metabolized by N-acetylation in rats, mice and monkeys. In an attempt to preclude metabolic N-acetylation sterically, we investigated LY201409, an analogue possessing two methyl groups ortho to the 4-amino substituent. This structural modification successfully altered the metabolic pathway, and LY201409 displayed potent anticonvulsant activity. LY201409 antagonized maximal electroshock (MES)-induced seizures with ED50 values of 16.2 and 4.2 mg/kg after oral administration to mice and rats, respectively. The compound did not effectively antagonize seizures induced by a variety of chemical convulsants in rats, but did block pentylenetetrazol-induced seizures in mice. Thus, among the classic anticonvulsants, the profile of phenytoin most closely resembles that of LY201409. Studies conducted with the rotorod and horizontal screen assays in mice and behavioral studies in rats suggested that doses of LY201409 that produced CNS side-effects such as sedation or ataxia were well separated from the anti-MES doses. LY201409 was a potent, dose-dependent potentiator of hexobarbital-induced sleeping time in mice. Oral administration of 6.0 mg/kg led to a 372% increase in sleep time relative to control values. Although LY201409 is a potent and effective anticonvulsant, it is also one of the most potent potentiators of hexobarbital-induced sleep time yet described.

Animals↗
PubMedDate not supplied

Comparative anticonvulsant activity and neurotoxicity of 4-amino-N-(2,6-dimethylphenyl)benzamide and prototype antiepileptic drugs in mice and rats.

The anticonvulsant and toxic properties of 4-amino-N-(2,6-dimethylphenyl)benzamide, (ADD 75073), were compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anticonvulsant test procedures. The results indicate that ADD 75073 is a very potent anticonvulsant in the maximal electroshock seizure (MES) model. The compound was effective in nontoxic doses following intraperitoneal (i.p.) administration in mice and oral administration in both mice and rats. In mice, the i.p. administration of ADD 75073 resulted in an ED50 value of 2.6 mg/kg as compared with a value of 9.5 mg/kg for phenytoin (PHT) in the same assay. Compound ADD 75073 was ineffective in nontoxic doses against all other seizure models examined in this study, and thus has a pharmacologic profile similar to that of PHT.

Animals↗
PubMedDate not supplied

Pharmacological effects of enantiomers of 4-amino-N-(alpha-methylbenzyl)benzamide, a chemically novel anticonvulsant.

LY 188544,S,R-4-amino-N-(alpha-methylbenzyl) benzamide, and its two stereoisomers are structurally novel anticonvulsants. The anticonvulsant profile of LY 188544 after intraperitoneal administration to mice was determined in standard anticonvulsant tests: maximal electric shock (MES), strychnine tonic-extensor, and threshold tests using pentylenetetrazol, picrotoxin, and bicuculline. In this series of tests, LY 188544 had good activity in the MES test and some activity in the three threshold tests. Thus, its profile of activity was most similar to that of phenobarbital, and less similar to that of phenytoin and carbamazepine. After oral administration to mice and rats, LY188544 was effective in the MES test, but did not provide complete protection in the threshold pentylenetetrazol test. When the individual stereoisomers, LY188545 (S isomer) and LY188546 (R isomer), were evaluated after oral administration, LY188545 was 2.2 times more potent than LY188546 against MES-induced seizures. However, when evaluated after intravenous administration, the potency difference was only 1.1. LY188546 was the least toxic in terms of neurological impairment. All compounds had good protective indexes (ratio between doses for neurological impairment and doses for anticonvulsant efficacy in the MES test). LY188545 and LY188546 potentiated hexobarbital sleeping time after acute administration but not after chronic (4-day) administration. Tolerance did not develop to the effects of LY188546 on MES or neurological impairment after 4 days of administration. These results suggest that LY188546 is a chemically novel anticonvulsant with a promising pharmacological profile.

Animals↗
PubMed1986

Antipsychotic effect of remoxipride, a new substituted benzamide with selective antidopaminergic activity.

Ten of 14 schizophrenic patients completed a 6-week pilot study with a new substituted benzamide, remoxipride. The final median dose was 600 mg/day (range 300-1200) corresponding to a plasma concentration of 5.16 mumol/l (1.55-11.50). Remoxipride reduced the psychotic symptomatology, especially hallucinations and delusions. The total Brief Psychiatric Rating Scale score decreased from 33.5 to 13.0 (P less than 0.01). Few side effects occurred; four patients had weak extrapyramidal symptoms, and four were slightly sedated. No cardiovascular side effects occurred. Prolactin increased, but apparently less than during sulpiride treatment.

Adult↗
PubMed1986

Comparisons between the in vitro binding of two substituted benzamides and two butyrophenones to dopamine-D2 receptors in the rat striatum.

The in vitro dopamine-D2 receptor binding profiles of two substituted benzamides (3H-sulpride and 3H-raclopride) and two butyrophenones (3H-spiperone and 3H-domperidone) were compared. 3H-Raclopride, 3H-domperidone and 3H-sulpride labelled approximately the same number of binding sites in the rat striatum, while 3H-spiperone labelled a higher number of binding sites. This latter finding was suggested to be due to the labelling of 5-HT2 receptors in addition to the dopamine-D2 binding sites since the labelling of these 5-HT2 receptors with 3H-spiperone could be avoided by the addition of the 5-HT2 receptor antagonist ketanserin. The inhibition constants (Ki) of the unlabelled compounds were similar to the Kd values obtained in the saturation analyses with 3H-raclopride, 3H-domperidone and 3H-sulpiride but were significantly higher when 3H-spiperone was used as radioligand. Addition of ketanserin to 3H-spiperone made the Ki values more similar to those obtained with the other radioligands. The implications of these findings in testing antidopaminergic activity is discussed.

Animals↗
PubMed1984

Investigation on central dopaminergic receptors (D-2) using the antagonistic properties of new benzamides.

The topography of the central dopaminergic receptor (D-2) has been studied using some analogues of tropapride, a new benzamide derivative, and sulpiride and clebopride as reference drugs. The compounds were compared by testing their ability to compete with [3H]spiperone in an in-vitro binding test and by measuring their potency as antagonists of apomorphine-induced climbing in mice. Tropapride was the most active compound, both in-vitro and in-vivo. With the amide group substituted in the 2-position of the tropane ring, the antidopaminergic activity of the compounds was much less than that of the 3-substituted derivatives. The interaction of the tropane derivatives with the D-2 receptor site is stereoselective as the equatorial stereoisomer was much more active than the axial isomer. The ethylene bridge present in the tropane derivatives but not in the corresponding piperidinyl analogues increases the affinity of the tropane derivatives for the D-2 receptor. Interaction with the D-2 receptor was confirmed as being Na+-dependent. The presence of a benzyl substituent on the basic nitrogen atom seems to be essential in the tropane series emphasizing the important role played in this series by the lipophilic auxiliary binding site postulated in Olson's model. In conclusion, the tropane skeleton may be considered a useful pharmacophoric group in the design of new dopaminergic drugs.

Animals↗
PubMed1996

Effects of sulpiride and nemonapride, benzamide derivatives having distinct potencies of antagonistic action on dopamine D2 receptors, on sensitization to methamphetamine in mice.

The acute ambulatory stimulation by methamphetamine (2 mg kg-1 S.C.) was dose-dependently reduced by 3-h pretreatment or combined treatment with sulpiride (1-100 mg kg-1 S.C.), and combined treatment with nemonapride (0.003-0.03 mg kg-1 S.C.), benzamide derivatives having selective antagonistic action on dopamine D2 receptors. The repeated (5 times) administrations of methamphetamine at 3-day intervals induced a sensitization to its ambulation-increasing effect, and the sensitization was significantly inhibited by 3-h pretreatment with either sulpiride (10-100 mg kg-1), or combined treatment with either sulpiride (3 or 10 mg kg-1) or nemonapride (0.01 or 0.03 mg kg-1) at each methamphetamine administration. Although the ambulation-increasing effect of methamphetamine disappeared by 3 h after the administration, the 3-h post-treatment with sulpiride (3 mg kg-1) or nemonapride (0.03 mg kg-1) after each methamphetamine administration was effective for a significant inhibition of the induction of methamphetamine sensitization, whereas, the comparatively higher doses of sulpiride (30 and 100 mg kg-1 in the combined treatment, and 10-100 mg kg-1 in the post-treatment) did not inhibit the methamphetamine sensitization. On the other hand, the repeated administrations of sulpiride (30 and 100 mg kg-1) alone, but not any doses of nemonapride, at 3-day intervals elicited a significant increase in the sensitivity to methamphetamine. These results suggest that, although the potencies of the anti-methamphetamine effects of sulpiride and nemonapride differ by a factor of 3000, they inhibit the induction of sensitization to methamphetamine in the pretreatment, combined treatment and early post-treatment schedules. However, it is also suggested that the repeated treatment with comparatively higher doses of sulpiride may produce a denervation supersensitivity of dopamine D2 receptors, and resultant increase in the sensitivity to methamphetamine.

Animals↗
PubMed2002

Characterization of nociceptin/orphanin FQ-induced pain responses by the novel receptor antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride.

At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. In the present study, we examined the involvement of the Noc/OFQ receptor in pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride (JTC-801). Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of JTC-801 with IC(50) values of 32.2 and 363 pg, respectively. JTC-801 did not induce allodynia by itself. Subcutaneous injection of formalin into a hindpaw evoked biphasic pain behaviors such as flinching and biting in mice. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, whereas it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1 microg. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by JTC-801 with an IC(50) value of 4.58 pg, the antinociceptive effects by 1 microg of Noc/OFQ were not antagonized by JTC-801. Furthermore, both phases of 2% formalin-induced pain behaviors were relieved by JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/OFQ receptor under physiological and pathophysiological conditions including pain.

Aminoquinolines↗
PubMed2004

SSR126768A (4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, hydrochloride): a new selective and orally active oxytocin receptor antagonist for the prevention of preterm labor.

4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide, hydrochloride (SSR126768A), a new potent and selective, orally active oxytocin (OT) receptor antagonist was characterized in several biochemical and pharmacological models. In binding studies, SSR126768A showed nanomolar affinity for rat and human recombinant and native OT receptors (K(i) = 0.44 nM) and exhibited much lower affinity for V(1a), V(1b), and V(2) receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 microM). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I(125)]d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8) (125)I-Tyr-NH(2)(9)]VT in situ labeling to OT receptors highly expressed in these tissues. In functional studies, SSR126768A behaved as a full antagonist and potently antagonized OT-induced intracellular Ca(2+) increase (K(i) = 0.50 nM) and prostaglandin release (K(i) = 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA(2) = 8.47). Similarly, in human pregnant myometrial strips, SSR126768A inhibited the contractile uterine response to OT. In conscious telemetrated rats, oral administration of SSR126768A (1-10 mg/kg) produced a competitive inhibition of the dose response to OT on uterine contractions up to 24 h at 3 mg/kg p.o.; no tachyphylaxis was observed after 4-day repeated treatment. Finally, SSR126768A (30 mg/kg p.o.) significantly delayed parturition in pregnant rats in labor similar to ritodrine (10 mg/kg p.o.). Thus, SSR126768A is a potent, highly selective, orally active OT receptor antagonist with a long duration of action. This molecule could find therapeutic application as a tocolytic agent for acute and chronic oral management of preterm labor.

Animals↗
PubMed2006

Effects of RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide], an orally active, selective dopamine D(3) receptor partial agonist in animal models of cocaine abuse.

Dopamine D(3) receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D(3) receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K(i) = 6.7 nM) and rat (K(i) = 1.6 nM) D(3) receptors with an intrinsic activity of approximately 50%. It possessed several hundredfold selectivity over the D(2) receptor. The molecule bound with moderate (100-250 nM) affinity to 5-hydroxytryptamine 1A (5-HT(1A)) and nonselectively labeled opiate receptors. RGH-237 proved to be practically inactive on more than 40 other targets, including monoaminergic, cholinergic, GABAergic, and glutamatergic receptors. In rats orally administered RGH-237 was well and rapidly absorbed yielding 41% oral bioavailability. At its pharmacologically active dose (10 mg/kg p.o.), the brain concentration of RGH-237 reached 110 ng/g. Its blood and brain levels were sustained for 3 h. RGH-237 at the oral dose of 10 mg/kg moderately but significantly inhibited the acquisition of cocaine-induced place preference, although by itself, it had no place-conditioning effect. The compound did not affect fixed ratio 1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration, the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behavior of rats at 10 and 30 mg/kg oral doses. RGH-237 did not affect seeking activity for natural rewards, such as sucrose and water. It did not exert notable effect on spontaneous motor activity of rats. Our results demonstrate that selective D(3) partial agonists may be an effective therapeutic means in the treatment of cocaine abuse.

Administration, Oral↗