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PubMed1988

Benzamides can stimulate as well as inhibit the activity of nuclear ADP-ribosyltransferase.

Benzamides are potent inhibitors of nuclear ADP-ribosyltransferase and have been extensively used to demonstrate the involvement of ADP-ribosylation in cellular function. When permeabilized L1210 cells are treated with 50 microM 3-acetylamidobenzamide (3-aab) the enzyme is inhibited. However, when 50 nM 3-aab is used a two-fold stimulation of enzyme activity is produced. This anomalous stimulation is obtained with benzamides and nicotinamides and is correlated with their activity as inhibitors. Strikingly the steady-state level of poly(ADP-ribose) in intact cells is increased by these low levels of inhibitors. The mechanisms of this effect and its consequences for the experimental use of benzamides are discussed.

ADP Ribose Transferases↗

PubMed2005

Alkylating benzamides with melanoma cytotoxicity: role of melanin, tyrosinase, intracellular pH and DNA interaction.

N-(2-Dialkylaminoethyl)benzamides have been shown to selectively accumulate in melanoma metastases with high uptake capacity. Therefore, this class of compound has previously been evaluated as a transporter for cytostatic drugs. It has been demonstrated that this significant targeting effect improves the cytotoxicity against melanoma cells. Although these agents are not accumulated by non-melanoma cells, they have been found to be toxic. In order to identify mechanistic reasons for this effect, we investigated the DNA and melanin binding affinities of a selection of four benzamide-drug conjugates, together with their parental cytostatics. An investigation of the influence of the melanin content on the cytotoxicity of these substances in B16 melanoma and Morris hepatoma (MH3924A) cells was performed, together with their influence on melanosomal pH and tyrosinase activity. The suppression of melanin formation with phenylisothiourea and the saturation of melanin binding sites with chloroquine were also investigated. These experiments demonstrated high DNA binding and low melanin affinity, in accordance with the toxicity against tumour cells. Melanin has a concentration-dependent scavenging effect, thereby reducing cytotoxicity. These compounds lead to an increase in the acidic pH of melanosomes, resulting in an increase in tyrosinase activity. The consequence of this reaction chain is an amplification of the scavenging effect for the benzamide-drug conjugates. These effects may be considered as limiting factors for the targeting characteristics of this class of compound, necessitating further modifications to the carrier system.

Animals↗

PubMed1984

Effect of lipophilicity of substituted benzamides on the dopaminergic effects in vivo and in vitro.

The antidopaminergic potencies of some new substituted benzamides related to remoxipride have been studied in the rat using in vitro (3H-spiperone binding) and in vivo techniques (antagonism of apomorphine induced stereotypies). The lipophilicities of the different benzamides were calculated by the addition of the lipophilic contribution (pi value) of the added substituent. It was found that the in vivo potencies of the compounds were not direct proportional to the in vitro potencies. The discrepancies in the potencies in vitro and in vivo (expressed as the ratio) are correlated to the calculated lipophilicities. Certain substituents in the benzene nucleus affect this in vitro--in vivo ratio more than could be expected from the change in lipophilicity caused by the substituent. The type of side chain is also of great importance. The reasons for the discrepancies between in vitro and in vivo antidopaminergic potencies of the studied substituted benzamides are discussed.

Animals↗

PubMed1998

Anticonvulsant profile of 4-amino-(2-methyl-4-aminophenyl)benzamide in mice and rats.

An original ameltolide analogue 4-amino-(2-methyl-4-aminophenyl)benzamide, in which a second amino group has been introduced, was synthesized and evaluated for anticonvulsant activity. After intraperitoneal administration to mice, 4-amino-(2-methyl-4-aminophenyl)benzamide was found active in the maximal electroshock seizure test and against the tonic seizures elicited either by bicuculline or 3-mercaptopropionic acid. 4-amino-(2-methyl-4-aminophenyl)benzamide (4A-2M4A-PB) gave anti maximal electroshock seizures ED50 of 63 micromol/kg (15.4 mg/kg) and a TD50 of 676 micromol/kg (163 mg/kg), yielding a PI of 10.7; the potency is similar to that of the 4-amino-(2-methyl-3-aminophenyl)phthalimide (4A-2M3A-PP), superior to that of 4-amino-(2,6-dimethylphenyl)phthalimide (4A-2,6-DMPP), close to that of phenytoin and carbamazepine and inferior to that of ameltolide. 4A-2M4A-PB with an ED50 of 41[28-60] micromol/kg (9.9 mg/kg) is as active after oral administration to rats as carbamazepine, more active than ameltolide, 4-A-2M3A-PP and phenytoin and slightly less active than the 4A-2,6-DMPP. The introduction of a second amino group on the substituted phenyl ring does not affect drastically the anticonvulsant potency after intraperitoneal administration to mice; moreover, it seems to enhance the activity after oral administration. 4A-2M4A-PB is a good candidate both for further pharmacokinetic studies and for the study of the precise mechanism of action.

Animals↗

PubMed1989

Definition of the in-vivo binding of [3H]spiperone in rat brain using substituted benzamide drugs.

The ability of some substituted benzamide drugs to define in-vivo the binding of [3H]spiperone to brain dopamine receptors in rats was assessed using behaviourally effective doses in comparison with haloperidol. As judged using haloperidol, [3H]spiperone identified dopamine receptors in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus, but not in frontal cortex or nucleus accumbens. The substituted benzamide compounds alizapride, metoclopramide, clebopride and YM 09151-2 prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. However, YM 09151-2 also caused displacement of [3H]spiperone accumulation in the nucleus accumbens and frontal cortex. (+/- )-Sulpiride, (+/- )-sultopride, amisulpiride and prosulpride all prevented the accumulation of [3H]spiperone in the hypothalamus but were ineffective in one or more of the other regions containing dopamine receptors defined by [3H]spiperone. The isomers of sulpiride and sultopride stereoselectively defined the accumulation of [3H]spiperone in dopamine containing brain regions. The (-)-isomers of both drugs prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. In contrast, (+)-sulpiride and (+)-sultopride were ineffective. Selected substituted benzamide drugs can be used to define the interaction of ligands with dopamine receptors in-vivo. These substances may be useful in PET studies in man. The isomers of some substituted benzamine drugs may be used to define dopamine receptors in-vivo by enantiomeric selectivity.

Amisulpride↗

PubMed1999

Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors.

Sigma receptors are known to be expressed in a variety of human tumor cells, including breast, neural, and melanoma tumors. A very high density (1.0-1.5 million receptors/cell) of sigma receptors was also reported in a human androgen-dependent prostate tumor cell line (LNCaP). In this study, we show that a very high density of sigma receptors is also expressed in an androgen-independent human prostate tumor cell line (DU-145). Pharmacological binding studies using the sigma-1-selective ligand [3H](+)-pentazocine showed a high-affinity binding (Kd = 5.80 nM, Bmax = 1800 fmol/mg protein). Similarly, binding studies with [3H]1,3-di-o-tolylguanidine in the presence of dextrallorphan also showed a high-affinity binding (Kd = 15.71 nM, Bmax = 1930 fmol/mg protein). Radioiodinated benzamide N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide ([125I]PIMBA) was also shown to bind DU-145 cells in a dose-dependent manner. Three different radioiodinated benzamides, [125I]PIMBA, 4-[125I]iodo-N-[2-(1'-piperidinyl)ethyl]benzamide, and 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide, were screened for their potential to image human prostate tumors in nude mice bearing human prostate cells (DU-145) xenografts. All three compounds showed a fast clearance from the blood pool and a high uptake and retention in the tumor. Therapeutic potential of nonradioactive PIMBA was studied using in vitro colonogenic assays. A dose-dependent inhibition of cell colony formation was found in two different human prostate cells. These results demonstrate the potential use of sigma receptor binding ligands in non-invasive diagnostic imaging of prostate cancer and its treatment.

Animals↗

PubMed1990

Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives.

Adult guinea pig hippocampal membranes contain two 5-hydroxytryptamine (5-HT) receptors positively coupled with an adenylate cyclase. One is a typical 5-HT1A receptor and the second is a nonclassical 5-HT receptor that we previously proposed to call 5-HT4. Here, we show that 4-amino-5-chlor-2-methoxy-benzamide derivatives are agonists of 5-HT4 receptors in guinea pig hippocampal membranes. Their effects on the adenylate cyclase of these membranes are not additive with those of 5-HT but are additive with those of RU 24969, a typical 5-HT1 agonist. The effects of benzamides, as well as those of 5-HT, on 5-HT4 receptors are not blocked by 5-HT1, 5-HT2, or 5-HT3 antagonists except ICS 205 903, which does so with a low affinity (1 microM). The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons.

Adenylyl Cyclases↗

PubMedDate not supplied

Metabolism, disposition, and pharmacokinetics of a potent anticonvulsant, 4-amino-N-(2,6-dimethylphenyl)benzamide (LY201116), in rats.

The metabolism, disposition, and pharmacokinetics of 4-amino-N-(2,6-dimethylphenyl)benzamide (LY201116) have been studied in rats. 14C-LY201116 was well absorbed (approximately 94%) from the gastrointestinal tract following oral administration. Of the dose administered, 64.5% was excreted in the urine and 29% in the bile; with the majority being excreted during the first 24 hr. Peak plasma levels of LY201116 were observed at 0.75 hr, whereas peak plasma concentrations of radioactivity were seen at 2 hr after dosing. Maximum levels of radioactivity were observed at 2 hr in all of the tissues studied. The elimination of radioactivity from the tissues was monophasic with a mean half-life of 3.4 hr. Biotransformation of LY201116 in rats was investigated by quantitating and isolating metabolites from urine and plasma. The major route of metabolism was N-acetylation to form 4-(acetylamino)-N-(2,6-dimethylphenyl)benzamide (ADMP), and subsequent hydroxylation to form 4-(acetylamino)-N-(2-hydroxymethyl-6-methylphenyl)benzamide (HADMP). Two hr after oral dosing with 14C-LY201116, ADMP and HADMP comprised 92% of the total radioactivity in the plasma. The major urinary metabolite, accounting for 63% of the radioactivity in the urine, was HADMP. The elimination of LY201116 from the systemic circulation following iv administration was monophasic, with a terminal t1/2 of 9.4 min. The volume of distribution was 911 ml/kg and the plasma clearance was 66.9 ml/min/kg.

Animals↗

PubMed1994

Scintigraphic detection of melanoma metastases with a radiolabeled benzamide ([iodine-123]-(S)-IBZM).

UNLABELLED: Iodine-123-(S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl] benzamide ([123I]-(S)-IBZM) is a radiolabeled benzamide usually employed to study neuropsychiatric disorders, such as schizophrenia and Parkinson's disease. The ectodermic origin of melanocytes and the presence of melanin in the substantia nigra are the theoretic basis of the experimental use of this class of tracers for melanoma imaging. METHODS: Eleven patients with proven metastatic melanoma entered the study. Whole-body and planar scintigrams were performed 2, 4 and 24 hr after intravenous injection of a mean tracer activity of 205 MBq. The dosimetric evaluation was performed by the Medical Internal Radiation Dose Committee method. RESULTS: The [123I]-(S)-IBZM scans allowed the detection of all six cutaneous lesions, five of six superficial pathologic lymph nodes, four of five pulmonary and one of two hepatic metastases. The maximum tumor-to-background ratio was 2.6 in planar images. The hepatobiliary excretion of the tracer may limit detection of intra-abdominal lesions. Dosimetry is similar to data for nononcologic patients. CONCLUSION: Although it is unclear if the mechanism of radiopharmaceutical uptake in melanoma is due to binding to membrane receptors or due to interactions with intracellular structures, radiolabeled benzamide is a promising tracer to detect melanoma.

Adult↗

PubMed1997

New benzamide-derived 5-HT3 receptor antagonists which prevent the effects of ethanol on extracellular dopamine, and fail to reduce voluntary alcohol intake in rats.

A set of substituted benzamides, characterized by the presence of a bulky quinolizidine moiety, were subjected to binding assays for 5-HT3 and D2 receptors on membranes obtained from the bovine area postrema ([3H]-GR65630) and the rat striatum ([3H]-spiperone) respectively. These benzamides resulted unsuitable for the recognition of D2 receptors, while a few of them, devoid of 5-HT4 receptor activity, had consistent affinity for central 5-HT3 receptors, inhibiting also potently the ethanol-induced dopamine efflux from the mesolimbic dopamine terminal region. However they failed in attenuating voluntary alcohol consumption in rats, as observed with several other chemically unrelated 5-HT3 antagonists. Thus the 5-HT3-mediated inhibition of alcohol-induced striatal release of dopamine by substituted benzamides is not a requisite for affecting ethanol intake.

Alcohol Drinking↗

PubMed2003

Stereospecific photochemical ring expansion of lithiated benzamides.

Treatment of N-benzyl benzamides with a strong base (LDA or t-BuLi) followed by irradiation with a 500 W tungsten lamp provides, according to the substitution pattern of the starting amides, either norcaradienes or cycloheptadienones by overall insertion of the N-benzyl group into the benzamide's aromatic ring system. Chiral benzamides undergo the ring expansion with high (sometimes complete) stereospecificity. The reaction appears to occur via a series of pericyclic reactions (photochemical or thermal sigmatropic rearrangements and thermal electrocyclic reactions) following an initial dearomatizing cyclization.

Journal Article↗

PubMed2002

Asymmetric synthesis of axially chiral benzamides and anilides by enantiotopic lithiation of prochiral arene chromium complexes.

Axially chiral benzamides and anilides were prepared by enantiotopic lithiation at the distinguished benzylic methyl of prochiral tricarbonylchromium complexes of N,N-diethyl 2,6-dimethylbenzamide (1) and N-methyl-N-acyl 2,6-dimethylaniline (14 and 21) with a chiral lithium amide base followed by electrophilic substitution in good yields with high optical purity. The resulting axially chiral chromium-complexed benzamides and anilides were oxidized under air to give chromium-free axially chiral benzamides and anilides in an enantiomerically active form without axial bond rotation at room temperature.

Journal Article↗

PubMed1996

Metabolism and action of benzamide riboside in Chinese hamster ovary cells.

Benzamide riboside (3-(1-deoxy-beta-D-ribofuranosyl)benzamide, BR) a new analog of nicotinamide riboside, is toxic to Chinese hamster ovary cells and inhibits guanine nucleotide synthesis in a manner comparable to that of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide). Adenosine kinase deficient cells demonstrate slight resistance but retain the ability to form the NAD analog, benzamide adenine dinucleotide (BAD). HPLC analysis of BAD containing cells is described. A BR resistant cell line was isolated that demonstrates cross-resistance to both tiazofurin and 6-aminonicotinamide, suggesting a common metabolic step; enzymatic analysis indicates reduced levels of NAD pyrophosphorylase in these cells. BR toxicity was only partially reversed or prevented by the presence of guanosine, suggesting either that BR inhibits guanine salvage to some extent or, more probably, that BR can, at high concentration, inhibit cell growth by another mechanism in addition to inhibition of guanine nucleotide synthesis. Cells incubated with BR for several hours retain the ability to salvage exogenously provided guanosine. The demonstration that BAD can be phosphorylated by NAD kinase, presumably to form BADP, suggests that this metabolite may be formed in cells and may have inhibitory activity at high concentrations of BR.

Animals↗

PubMed1999

Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4- pyrrolidinyl]benzamide (TKS159) and its optical isomers.

Of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4- pyrrolidinyl)benzamide, four optical isomers, (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, were prepared from optically active 4-amino-1-ethyl-2-hydroxymethylpyrrolidine di-p-toluenesulfonate [(2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, respectively]. The requisites, (2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R,4R)-23, were prepared from a commercially available trans-4-hydroxy-L-proline. The absolute configurations of (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27 were spectroscopically determined. Of the benzamide derivatives, four optical isomers, (2S,4S)-1, (2S,4R)-25, (2R,4S)-26 and (2R,4R)-27, showed a relatively potent affinity for 5-hydroxytryptamine 4 (5-HT4) receptors in a radioligand binding assay ([3H]GR113808). The activities of 25-27 were less effective than that of 1 for the gastric emptying of a phenol red semisolid meal in rats. All this suggests that the most potent of the isomers was 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2- hydroxymethyl-4-pyrrolidinyl]benzamide (1).

Animals↗

PubMed1996

Comparison of two fluorine-18 labeled benzamide derivatives that bind reversibly to dopamine D2 receptors: in vitro binding studies and positron emission tomography.

The purpose of the present set of studies was to characterize, in vitro and in vivo, two benzamide analogues, 2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin4yl]benzamide (MBP) and 4'-fluoroclebopride (FCP), for studying dopamine D2 receptors with Positron Emission Tomography (PET). In vitro binding studies were conducted to determine the affinities of MBP and FCP to the three subtypes of dopamine D2 receptors: D2(long), D3, and D4 receptors. MBP was found to have a high affinity (Ki = 1-8 nM) for all three subtypes of the D2 receptor, whereas FCP had nanomolar affinity (Ki approximately 5.5 nM) for D2(long) and D3 receptors, and a lower affinity for D4 receptors (Ki = 144 nM). In vitro binding studies also revealed that MBP had a relatively high affinity for rho1 receptors (Ki = 11 nM) compared to FCP (Ki = 340 nM). PET imaging studies were conducted in rhesus monkeys with the fluorine-18 labeled analogues of each compound. Both [18F]MBP and [18F]FCP displayed reversible binding kinetics during the 3 h time course of PET. [18F]FCP was found to have a higher basal ganglia:cerebellum ratio and lower variability in the rate of washout from D2 receptors in vivo relative to [18F]MBP. Neither radiotracer was found to produce radiolabeled metabolites capable of crossing the blood-brain barrier. The high rho1 binding affinity and low basal ganglia:cerebellum ratio of [18F]MBP indicate that this ligand may not be suitable for quantitative studies of D2 receptors. The results from the in vitro and in vivo studies indicate that [18F]FCP is a promising ligand for studying D2 receptors with PET.

Animals↗

PubMed2004

Pharmacokinetics and splenic accumulation of N-acetylamino-3-chloro-N-(2-diethylamino-ethyl) benzamide after a single administration to rats.

The purpose of this study was to measure the pharmacokinetics and tissue accumulation of N-acetylamino-3-chloro-N-(2-diethylamino-ethyl) benzamide (NACPA) after oral or intravenous administration at a single dose of 25 mg/kg to female W/Fu rats. The serum pharmacokinetics of NACPA were characterized by rapid absorption, distribution and elimination. However, in comparison with its parent compound, 4-amino-3-chloro-N-(2-diethylamino-ethyl) benzamide (3-CPA), NACPA displayed a higher Cmax (mean+/-SD, 201+/-21 vs 33.6+/-0.5 nmol/ml, p < 0.05), and a longer elimination half-life (50+/-0.8 vs 36.6+/-1.1 min, p < 0.05) following intravenous administration. Bioavailability of NACPA was significantly greater than that of 3-CPA (50% compared with 14%, p < 0.05). The tissue accumulation of NACPA was generally higher than that of 3-CPA. NACPA was deposited at higher concentrations in the spleen than in the kidney and liver. Cellular pharmacokinetics indicated that NACPA accumulated more readily in lymphocyte related cells than in liver related cells. Furthermore, incubation of human peripheral lymphocytes with NACPA resulted in inhibition of lymphocyte proliferation, INF-gamma production and chemotaxis. All these results suggest that NACPA may be a good candidate drug for oral administration for immune modulation.

Animals↗

PubMed1995

PET imaging studies of dopamine D2 receptors: comparison of [18F]N-methylspiperone and the benzamide analogues [18F]MABN and [18F]MBP in baboon brain.

A series of positron emission tomography (PET) imaging studies was conducted in a baboon with the benzamide derivatives [18F]2,3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3.1]non an-3 beta-yl]benzamide ([18F]MABN) and [18F]2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]be nza mide ([18F]MBP). Studies were also conducted with the butyrophenone [18F]N-methylspiperone (NMSP) for comparison. Tissue-time activity curves of [18F]MABN are similar to those of [18F]NMSP since both compounds displayed approximately the same uptake in the basal ganglia and displayed irreversible binding kinetics in vivo. However, the rapid rate of clearance from the cerebellum and high basal ganglia:cerebellum ratio of [18F]MABN indicate that this compound has a much lower amount of nonspecific binding than [18F]NMSP. [18F]MBP displayed a higher uptake in the basal ganglia relative to [18F]NMSP and [18F]MABN and exhibited reversible binding kinetics in vivo. This property of [18F]MBP is desirable since the uptake of radioactivity in D2-rich ligands is less likely to be influenced by changes in cerebral blood flow. The current data suggest that both [18F]MABN and [18F]MBP are promising ligands for studying dopamine D2 receptors with PET.

Animals↗

PubMed2002

The genes gmdA, encoding an amidase, and bzuA, encoding a cytochrome P450, are required for benzamide utilization in Aspergillus nidulans.

Two unlinked loci, gmdA and bzuA, have previously been identified as being required for the utilization of benzamide as the sole nitrogen source by Aspergillus nidulans. We have cloned each of these genes via direct complementation. The gmdA gene encodes a predicted product belonging to the amidase signature sequence family that displays similarity to AmdS from A. nidulans. However, identity is significantly higher to the amdS gene from Aspergillus niger. The bzuA gene encodes a protein belonging to the cytochrome P450 superfamily and is orthologous to the benzoate para-hydroxylase-encoding gene bphA of A. niger. The bzuA1 mutation prevents the use of benzoate as a carbon source and intracellular accumulation of benzoate results in growth inhibition on benzamide. Northern blot analysis has shown that gmdA expression is subject solely to AreA-dependent nitrogen metabolite repression while bzuA is strongly benzoate inducible and subject to CreA-mediated carbon catabolite repression and a probable inactivation of benzoate induction by glucose. Fluorescence microscopy of a fusion of the N-terminal end of BzuA to green fluorescent protein revealed that this protein localizes to the endoplasmic reticulum.

Amidohydrolases↗