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At least 235 records · Page 13Linked to original sources
PubMed1982

Pharmacological studies on a new benzamide derivative, YM-09151-2, with potential neuroleptic properties.

The electrophysiological properties and cataleptogenicity of YM-09151-2 (N-[(2RS, 3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-methoxy-4-methylaminobenzamide) were studied in the cat. This drug inhibited the EEG arousal response to electrical stimulation of the mesencephalic reticular formation with the same potency as that of haloperidol, whereas chlorpromazine revealed a more potent central depressant action. The duration of the afterdischarge induced by electrical stimulation of the amygdaloid nucleus was initially shortened and thereafter prolonged by both YM-09151-2 and haloperidol. However, YM-09151-2 was less effective than haloperidol and chlorpromazine in both augmenting the spindle bursts produced by electrical stimulation of the caudate nucleus and antagonizing the inhibitory effect of L-DOPA on the caudate spindle, indicating a smaller effect of YM-09151-2 on the extrapyramidal dopaminergic system than that of the two neuroleptic drugs. In fact, YM-09151-2 produced no cataleptic behaviour in the cat even at a dose of 5 mg/kg (s.c.), although haloperidol and chlorpromazine caused catalepsy in doses of 0.5 and 5 mg/kg (s.c.), respectively. Sulpiride, chemically related to YM-09151-2, showed much weaker central actions than YM-09151-2. The results indicate that a new benzamide, YM-09151-2, has a potent neuroleptic effect with a slight central depressant activity and that the cataleptogenicity of the compound is weaker than that of haloperidol and of chlorpromazine.

Amygdala↗
PubMed1986

Dopamine D2 receptors and dopamine metabolism. Relationship between biochemical and behavioural effects of substituted benzamide drugs.

The effect of the substituted benzamide dopamine D2 receptor antagonists sulpiride, raclopride, FLA 966(-), FLA 988(-), eticlopride and remoxipride as well as the "classical" dopamine antagonists, haloperidol and chlorpromazine, on the concentrations of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain of the rat was investigated. All compounds increased the turnover of dopamine, as defined by increased concentrations of DOPAC and HVA (without change in the concentration of dopamine) in the striatum in a dose-dependent manner. The doses of the compounds producing increased turnover of dopamine in the striatum were in the same range as those displacing the in vivo binding of [3H]spiperone in the striatum. In addition, for all the compounds tested in the study, an increase in the turnover of dopamine to about 300% of control was observed for doses antagonising the stereotypy produced by the dopamine agonist, apomorphine. On the other hand, no consistent relationship between increased turnover of dopamine and the doses of the compounds required to antagonise apomorphine-induced hyperactivity was found. This result was also found in limbic areas. Remoxipride and haloperidol had little or no effect on the turnover of dopamine in either the hypothalamus or substantia nigra at the ED50 doses of these compounds for antagonism of apomorphine-induced stereotypy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Synthetic and pharmacological studies on some transition metal chelates involving N-pyrimidino benzamide-2-carboxylic acid as ligand.

N-pyrimidino benzamide-2-carboxylic acid (NPBCA) and its Cu(II), Ni(II), Co(II), Zn(II), and Mn(II) chelates have been synthesized and characterized by using elemental analyses, molar conductance, molecular weight determination, magnetic moment, infrared, and electronic spectra. Antifungal activity of the synthesized compounds has been screened on common fungi, viz., Aspergillus niger, Aspergillus nidulense, and Candida albicans at 28 degrees C and antibacterial activity has been observed on gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria at 37 degrees C. Anti-inflammatory and ulcerogenic potential of the synthesized compounds have been discussed.

Animals↗
PubMed1989

Influence of benzamide on killing and mutation of density-inhibited V79 cells by MNNG.

Density-inhibited V79 cells when held for 24 h in complete medium after exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) show improved survival levels and decreased mutant frequencies at all dose levels, compared to cells not so held. However, when benzamide, an inhibitor of poly(ADP-ribose) synthesis was present during this 24-h holding, the improvement in survival and decrease in mutant frequencies were not observed. Rather, compared to the control, the cells became more sensitive to MNNG and mutant frequency also increased significantly for all doses studied.

Animals↗
PubMed1986

Preferential tumor radiosensitization by analogs of nicotinamide and benzamide.

The effects of a range of different analogs of nicotinamide and benzamide on the X ray response of the EMT-6 tumor in vivo was investigated. Using an in vivo/in vitro survival assay, sensitization was seen at a dose of 2 mmole/kg for all but one of the analogs tested. The enhancement ratios (ER's) ranged from 1.0 to 1.5. Of particular interest were nicotinamide and SR-4350 which gave large ER's (1.5 and 1.4 respectively) at doses which were only about 12% of the LD50 values. In one normal tissue studied (skin reaction) a large single dose of nicotinamide (8 mmole/kg) only gave an ER of 1.1. These results will be discussed with reference to the mechanisms involved and the clinical implications.

Animals↗
PubMed1991

Fluorinated benzamide neuroleptics--2. Synthesis and radiosynthesis of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-3- substituted-2-methoxybenzamides.

Synthesis of a fluorinated benzamide neuroleptic, (S)-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(3-fluoropropyl)-2,3- dimethoxybenzamide starting from 3-(3,4-dimethoxyphenyl)-1-propanol in 20-25% overall yield is reported. Radiosynthesis of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]- 5-(3[18F]fluoropropyl)-2-methoxybenzamide([18F]FPHB) and (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3[18F]fluoropropyl)-2,3- dimethoxybenzamide([18F]FPHB) was carried out by nucleophilic substitution reaction of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl-5-(3-tosyloxypropyl)-2-me tho xybenzamide and (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-tosyloxypropyl)-2,3- dimethoxybenzamide respectively, with no carrier added [18F]fluoride. Both, [18F]FPHB and [18F]FPHB were obtained in approx. 20-30% yields (EOS/EOB, decay corrected). Specific activities of 900-1700 Ci/mmol for [18F]FPHB and 800-1400 Ci/mmol for [18F]FPMB were obtained by reverse phase HPLC purification. Total synthesis and purification time required for either [18F]FPHB or [18F]FPMB was 120 min from EOB.

Antipsychotic Agents↗
PubMed1990

Optically active benzamides as predictive tools for mapping the dopamine D2 receptor.

Substituent variations on the pyrrolidinyl nitrogen of sulpiride, a selective D2 dopamine antagonist, showed that in vitro and in vivo activities are concentrated in the (S) optical series for N-alkyl analogs and in the (R) series for N-benzyl analogs. To account for these unusual structure-activity relationships, a pharmacophoric model was built from the crystallographic structure of (-)piquindone and extended to 14 other D2 antagonists. This model considers the lone pair orientation of the basic nitrogen rather than its spatial location. Two distinct active conformations for benzamides were defined, corresponding to the (S) and (R) series. An extended pharmacophore is then proposed involving four main anchoring areas: (i) an aromatic site Ar1, (ii) a tertiary nitrogen with its lone pair orthogonal to the Ar1 plane, (iii) a dipole delta 1 coplanar to the Ar1 ring and (iv) three sites for the N-substituent, including a small hydrophobic pocket and two different aromatic binding sites Ar2 and Ar3. To probe the predictive value of this model, structures were designed and several compounds were synthesized and tested as inhibitors of [125I]iodo-sulpiride binding to rat striatal membranes and as antagonists of apomorphine-induced stereotyped behavior in mice.

Animals↗
PubMed1993

Synthesis and biological evaluation of radioiodinated N-2-(4-piperidyl)ethyl benzamides.

Three iodinated benzamides, 5-7, analogues of the potent acetylcholinesterase inhibitor 1-benzyl-4-[N-[4'-(benzylsulfonyl) benzoyl-N-methylamino]ethyl]piperidine (2), were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, receptor screening revealed that compounds 5-7 exhibit nanomolar affinity for the sigma binding site. Both [125I]5 and [125I]7 were synthesized and evaluated in rats. Following the intravenous administration of [125I]5 into rats, 1.59% of the injected dose was found in the rat brain within 5 min. The level of radioactivity in the brain remained steady for 2 h, the duration of the study. In contrast, 0.42% of the injected dose was detected in the rat brain following the i.v. injection of [125I]7. Coadministration of either [125I]5 or [125I]7 with 0.5 mumol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [123I]5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [123I]5 may be potentially useful for studying sigma receptor distribution in the human brain.

Animals↗
PubMed1996

Synthesis, in vitro binding profile and biodistribution of a 125I-labeled N-benzyl pyrrolidinyl benzamide derivative: a potential radioligand for mapping dopamine D2 receptors.

cis-N-(1-Benzyl-2-methylpyrrolidine-3-yl)-5-iodo-2-methoxy-4-(methylamin o) benzamide (IYM), a YM-09151-2 analog iodinated at the 5-position of the benzoyl moiety, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain dopamine D2 receptors by single photon emission computer tomography (SPECT). [125I]IYM was synthesized by a halogen exchange reaction and purified by high-performance liquid chromatography (HPLC). An in vitro competitive binding study with [3H]spiperone using rat striatal synaptosomal membranes revealed that IYM had higher affinity for dopamine D2 receptors than did YM-09151-2 or spiperone. In a saturation binding study using rat striatal synaptosomal membranes, IYM had a Kd of 0.04 nM. Biodistribution studies in mice disclosed that [125I]IYM exhibited high and specific striatal uptake, with the striatal/cerebellar uptake ratio being 14 at 120 min after injection. Furthermore, the striatal uptake of [125I]IYM was saturable, and [125I]IYM was displaced only by dopaminergic compounds. Ex vivo autoradiographic studies in rats further confirmed the high uptake and retention of this agent in the striatum and total blockade of its uptake by YM-09151-2. Thus, IYM showed specific binding to dopamine D2 receptors in the rodent striatum and therefore holds great potential for use in in vivo dopamine D2 receptor studies.

Animals↗
PubMed1989

Differential response of excision proficient and deficient L5178Y cells to UVC irradiation and benzamide.

L5178Y-R and L5178Y-S cells differ in sensitivity to UVC radiation (D0 values: 2.8 and 9.0 J m-2 respectively, exposure in Fischer's medium). The UVC sensitivity is related to the excision repair ability. Benzamide (Bz), an inhibitor of adenosine diphosphoribosyl transferase (ADPRT), does not modify the lethal effect of UVC radiation in L5178Y-R cells, whereas it sensitizes L5178Y-S cells. The content of NAD+ after irradiation decreases only in the latter cells and this decrease can be prevented by 2 mM Bz treatment. In agreement with the survival data, in L5178Y-R cells neither the proportion of abnormal cells nor the frequency of chromatid aberration are affected by 2 mM Bz treatment, in contrast with L5178Y-S cells. Bz slightly reverses inhibition of 3H-thymidine incorporation only in L5178Y-S cells, but it does not affect the proportions of cells in the different phases of the cell cycle in either cell strain after UVC exposure. These data could be taken as an indirect indication of the involvement of ADPRT in DNA repair in UVC-irradiated L5178Y-S cells. However, the increase in the number of DNA strand breaks in UVC-exposed, Bz-treated cells compared with UVC-exposed untreated cells is the same in both L5178Y strains.

Animals↗
PubMed2006

Synthesis, discovery and mechanism of 2,6-dimethoxy-N-(4-methoxyphenyl)benzamide as potent depigmenting agent in the skin.

In this study, a new skin-depigmenting agent, 2,6-dimethoxy-N-(4-methoxyphenyl)benzamide (DMPB), was synthesized using a combination of benzoic acid and aniline. DMPB exhibited significant depigmentation ability on the UV B-induced hyperpigmentation of the brown guinea pig skin. In addition, the 100ppm treatment with this compound had a 30% inhibitory effect on melanin pigment generation in the melan-a cell line without significant cell toxicity. To search for relationship with the depigmentation, the effects of DMPB on the tyrosinase and dopachrome tautomerase were evaluated. DMPB had no effect on tyrosinase. However, it accelerated dopachrome transformation into 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in the presence of dopachrome tautormerase. In addition, intracellular level of dopachrome tautomerase in melan-a cells was increased by treatment of DMPB. These results suggest that the pigment-lightening effects of DMPB might be due to biased production of DHICA-eumelanin induced by dopachrome tautormerase activation.

Aniline Compounds↗
PubMed2004

QSPR/QSAR in N-[(dimethylamine)methyl] benzamides substituents groups influence upon electronic distribution and local anesthetics activity.

It was determined, with a systematic mode, the carbonyl group frequency in the region of the infrared of N-[(dimethylamine)methyl] benzamides 4-substituted (set A) and their hydrochlorides (set B), that had its local anesthetical activity evaluated. The application of the Hammett equation considering the values of the absorption frequency of carbonyl group, nu(C=O,) using the electronic constants sigma, sigma(I), sigma(R), I and R leads to meaningful correlation. The nature and the contribution of substituent group electronic effects on the polarity of the carbonyl group was also analyzed. The use of the nu(C=O) as an experimental electronic parameter for QSPR studies was validated.

Anesthetics, Local↗
PubMed2004

Synthesis and pharmacological properties of benzamide derivatives as selective serotonin 4 receptor agonists.

A series of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamides with a polar substituent group at the 1-position of the piperidine ring was synthesized and evaluated for its effect on gastrointestinal motility. The benzoyl, phenylsulfonyl, and benzylsulfonyl derivatives accelerated gastric emptying and increased the frequency of defecation. One of them, 4-amino-N-[1-[3-(benzylsulfonyl)propyl]piperidin-4-ylmethyl]-5-chloro-2-methoxybenzamide (13a, Y-36912), was a selective 5-HT4 receptor agonist offering potential as a novel prokinetic with reduced side effects derived from 5-HT3- and dopamine D2 receptor-binding affinity. In the oral route of administration, this compound enhanced gastric emptying and defecation in mice, and has a possibility as a prokinetic agent, which is effective on both the upper and the lower gastrointestinal tract.

Animals↗
PubMed2006

Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides.

N(1)-Phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (1) and N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (2) show potent in vitro antimitotic activity against kinetoplastid parasites but display poor in vivo activity. Seventeen new dinitroaniline sulfonamide and eleven new benzamide analogs of these leads are reported here. Nine of the sulfonamides display in vitro IC(50) values under 500 nM against African trypanosomes, and the most active antikinetoplastid compounds also inhibit the in vitro assembly of purified leishmanial tubulin with potencies similar to that of 2. While several of the potent compounds are rapidly degraded by rat liver S9 fractions in vitro, N(1)-(3-hydroxy)phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (21) displays an IC(50) value of 260 nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay.

Animals↗
PubMed2004

N,N-dialkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides, potent, selective delta opioid agonists.

A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity.

Analgesics, Opioid↗
PubMed2004

Parallel methods for the preparation and SAR exploration of N-ethyl-4-[(8-alkyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-aryl-methyl]-benzamides, powerful mu and delta opioid agonists.

Two parallel synthetic methods were developed to explore the structure-activity relationships (SAR) of a series of potent opioid agonists. This series of tropanylidene benzamides proved extremely tolerant of structural variation while maintaining excellent opioid activity. Evaluation of several representative compounds from this series in the mouse hot plate test revealed potent antinociceptive effects upon oral administration.

Analgesics↗