SEARCH · PubMed Health

Results for “Benzamides”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

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↗

PubMed1994

Analysis of neurogenic contractions induced by ML-1035 and other benzamides in the guinea-pig non-stimulated isolated ileum.

4-Amino-5-chloro-substituted benzamides have been shown to increase gastric motility in-vivo and enhance field-stimulated and peristaltic contractions in-vitro. The present experiments examined the contractile response to a series of benzamides in the guinea-pig non-stimulated ileum. Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine (% acetylcholine response = 12 +/- 2, 19 +/- 3, 26 +/- 2, 51 +/- 3, n = 13, 8, 17, and 21, with EC50 values of 0.85, 1.8, 5.7, and 14.2 microM for cisapride, zacopride, metoclopramide, and ML-1035 (4-amino-5-chloro-2-((2-methylsulphinyl)-ethoxy)-N- (2-(diethylamino)-ethyl)-benzamide hydrochloride), respectively). ML-1035 contractions were completely blocked by atropine and tetrodotoxin, while ganglionic blockade with hexamethonium was ineffective. Metoclopramide has been reported to sensitize postjunctional muscarinic receptors, however, ML-1035 did not enhance acetylcholine-induced contractions. Tropisetron (ICS 205-930, 1 microM), caused a parallel rightward shift in the concentration-response curve for both ML-1035 and zacopride (EC50 = 14.2 +/- 1.3 and 1.8 +/- 0.8 microM in the absence, and 26 +/- 2.7 and 6.9 +/- 2.3 microM in the presence of tropisetron for ML-1035 and zacopride, respectively) with apparent pKB values of 5.9 and 6.0 for the respective compounds. 5-Hydroxytryptaminergic receptor desensitization by 2-methyl-5-hydroxytryptamine (5-HT3) and 5-methoxytryptamine (5-HT4), attenuated the response to ML-1035.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1983

Enhancement of antitumor activity of bleomycin by benzamide in vitro and in vivo.

The cytotoxic effects of bleomycin on HeLa cells in culture were enhanced by incubation of the cells with benzamide, a potent inhibitor of poly(ADP-ribose) polymerase, at concentrations at which benzamide alone did not show any cytotoxicity. Benzamide plus bleomycin display enhanced therapeutic effects against Ehrlich ascites tumor cells in vivo. On daily treatment with various doses of bleomycin plus benzamide for 10 days, mice with Ehrlich ascites tumors survived longer than mice on treatment with bleomycin alone.

Animals↗

PubMed1999

Newly discovered anti-inflammatory properties of the benzamides and nicotinamides.

Our laboratory has concentrated on the possible regulation the benzamides and nicotinamides may have on the processes of DNA repair and apoptosis. Recent reports have suggested that both apoptosis and inflammation are regulated by the transcription factor NF-kappaB. We have initiated studies regarding the hypothesis that the benzamides and nicotinamides could inhibit the production of tumor necrosis factor alpha (TNFalpha) and the inflammatory response as well as induce apoptosis via inhibition of NF-kappaB. Our data have shown that nicotinamide and two N-substituted benzamides, metoclopramide (MCA) and 3-chloroprocainamide (3-CPA), gave dose dependent inhibition of lipopolysacharide induced TNFalpha in the mouse within the dose range of 10-500 mg/kg. Moreover, lung edema was prevented in the rat by 3 x 50 mg/kg doses of 3-CPA or MCA, and 100-200 microM doses of MCA could also inhibit NF-kappaB in Hela cells. Taken together these data strongly support the notion that benzamides and nicotinamides have potent anti-inflammatory and antitumor properties, because their primary mechanism of action is regulated by inhibition at the gene transcription level of NF-kappaB, which in turn inhibits TNFalpha and induces apoptosis.

Animals↗

PubMed1998

Correspondence analysis of protein kinase C (PKC) inhibition by bis-basic substituted benzamides.

We describe the synthesis of a novel series of bis-basic substituted benzamides and their relative potency in inhibiting rat brain protein kinase alpha (PKC alpha) activity. None of the compounds inhibited enzyme activity via the catalytic domain but several did via the regulatory domain at 1-5 microM concentrations. Inhibition was comparable to that of several di- and triphenylacrylonitriles and triphenylethylenes. According to a multivariate factor (correspondence) analysis of QSAR descriptors, hydrophobicity (log p) and hydration energy were the most discriminant descriptors, much more so than molecular mass, molar refractivity, polarizability, molecular volume and solvent-accessible surface. Inhibitory activity was correlated with high hydrophobicity and low hydration energy. The higher potency of GL9 (N,N'-oxalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide]) that differed from its congener (GL25) by the presence of an oxamide rather than succinamide moiety was tentatively explained by the greater negative charges associated with the carbonyl groups of its oxamide residue. The higher potency of GL22 (N,N'-tere-phthalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide ] in which an aromatic ring is inserted between two benzamide moieties in para, para' rather than ortho, ortho' positions as in GL23 might be due to a planar conformation facilitating membrane insertion. In conclusion, correspondence analysis is a neat way of highlighting similarities and differences in molecular properties (QSAR descriptors and potency). Therapeutic doses of many classes of drug might interfere with the regulatory domain of PKC alpha if, like our test-compounds, they have basic side-chain(s), high hydrophobicity, low hydration energy, a planar conformation and/or a highly charged reactive (oxamide) moiety.

Animals↗

PubMed1983

Stimulation of poly(ADP-ribosyl)ation during Ehrlich ascites tumor cell "starvation" and suppression of concomitant DNA fragmentation by benzamide.

Incubation of Ehrlich ascites tumor cells in their own ascites fluid induced a reversible metabolic adaptation to these "starvation" conditions which was associated with a fragmentation of DNA. Endogenous poly(ADP-ribose) residues also increased, reaching within 1-3 h values 6-10 times higher than in cells taken directly from the mouse peritoneum. The NAD content changed only slightly while dimethyl sulfate-induced accumulation of poly(ADP-ribose) (10-fold within 30 min) was associated with a rapid depletion of NAD (85% lost at 30 min). Nevertheless, turnover of poly(ADP-ribose) as measured by the decay rate of the polymer upon addition of benzamide was dramatically stimulated in both situations, reaching apparently identical half-lives (t 1/2 approximately equal to 1 min) in "starved" and in alkylated cells. However, since penetration of benzamide into the nucleus may be the rate-limiting factor in these studies, turnover of poly(ADP-ribose) in dimethyl sulfate-treated cells may still be much higher than that in "starved" cells. In cells treated with dimethyl sulfate, suppression of poly(ADP-ribose) synthesis by benzamide did not interfere with DNA fragmentation or with DNA resealing as determined by the nucleoid procedure. By contrast, starvation induced a type of DNA incision that was prevented by benzamide. It is proposed that starvation-induced scission of DNA occurs at specific ("regulatory?") sites requiring poly(ADP-ribose) formation to take place, while fragmentation of DNA at random as seen with alkylating agents is associated with, but not dependent on, increased poly(ADP-ribosyl)ation.

Animals↗

PubMed2000

Synthesis of axially chiral benzamides utilizing tricarbonyl(arene)chromium complexes.

Axially chiral N,N-diethyl 2,6-disubstituted benzamides were stereo-selectively prepared utilizing planar chiral (arene)chromium complexes as an enantiomerically active form by following two methods. Ortho-lithiation of the enantiomerically pure planar chiral tricarbonyl(N,N-diethyl 2-methylbenzamide)chromium complex followed by electrophilic quenching gave axially chiral 2-methyl-6-substituted N,N-diethyl benzamide chromium complexes. Photo-oxidative demetalation produced the chromium-free axially chiral benzamides as optically active compounds. An alternative method for the preparation of axial chiral benzamides is an enantioselective lithiation at the benzylic methyl of meso tricarbonyl(N,N-diethyl 2,6-dimethylbenzamide)chromium with appropriate chiral lithium amide base followed by quenching with alkyl halides.

Journal Article↗

PubMed1992

Comparison of pyrrolidinyl and piperidinyl benzamides for their anticonvulsant activity and inhibitory action on sodium channel.

1. A pair of benzamide analogues containing a pyrrolidinyl or piperidinyl group was examined for their anticonvulsant activity against the electroshock-induced seizures in mice and the ability to block the voltage-gated Na channel in N1E-115 cells, in comparison with the prototype compound, U-54494A, (+/-)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-ben zam ide , a potent anticonvulsant and a Na channel blocker. 2. The pyrrolidinyl benzamide (U-49524E) was found to be effective against the electroshock-induced seizures (ED50 = 35 mg kg-1, i.p.) whereas the benzamide with a piperidinyl moiety (U-49132E) was inactive (ED50 greater than 100 mg kg-1). 3. Using whole-cell patch clamp techniques we found that U-49132E was several times less potent, with an IC50 of 396 microM as compared to 118 microM for U-49524E at the holding potential of -80 mV, and was much slower in blocking Na channels with a half-time of 10.7 +/- 1.1 min vs. 2.2 +/- 0.4 min for its counterpart. 4. Qualitatively, their general modes of interaction with Na channels were similar to each other and to that of U-54494A in that they interacted with the resting and slowly-inactivated states of the channels and exhibited a use-dependent inhibition because of a slow recovery from the inactivated state in the presence of the drugs. 5. Comparison of their physicochemical properties, shows the less potent and slowly acting U-49132E is more hydrophobic and bulkier than U-49524E, but has the same pKa. This suggests that the drugs approach the Na channel through a narrow and hydrophilic pathway.6. Overall, this study underscores the importance of inhibiting the Na channel to the anticonvulsant activity of the benzamide compounds.

Animals↗

PubMed2002

Studies on the mechanism of action of benzamide riboside: a novel inhibitor of IMP dehydrogenase.

Benzamide is a well known inhibitor of poly(ADP-ribose)polymerase, an enzyme involved in DNA repair. However, benzamide exhibited neuotoxicity in animals and hence, in the hope of overcoming this problem, benzamide riboside (BR) was synthesized. Our mechanism of action studies on BR suggested that the agent was being metabolized to its 5'-monophosphate and then to its NAD analogue (BAD, benzamide adenine dinucleotide) that inhibits Inosine 5'-monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting enzyme of the branched purine nucleotide synthetic pathway that provides guanylates including GTP and dGTP. There are two isoforms of IMPDH, type I that is constitutively present in all cells, and type II that is inducible and is present in highly proliferating cells such as cancer. Ongoing studies with BR analogues suggest that they are more selective in inhibiting IMPDH type II. Our studies have characterized the metabolites of BR, especially its NAD analogue, BAD, by synthesizing this active metabolite by enzymatic means, and identifying its structure by NMR and mass spectrometry. We have partially purified IMPDH from tumor cells and have examined the kinetics of inhibition of IMPDH by BAD. We have also compared biochemical and cytotoxic activities of BR with tiazofurin and selenazofurin, that share similar mechanisms of action with BR. Our studies demonstrated that 2-3-fold more BAD is formed compared to TAD and SAD, the active metabolites of tiazofurin and selenazofurin, respectively. BR has demonstrated potent cytotoxic activity in a diverse group of human tumor cells, specifically more active in sarcomas and CNS neoplasms compared to tiazofurin or selenazofurin. Future in vivo animal studies should set a stage for determining its effectiveness in clinical Phase I studies.

Antineoplastic Agents↗

PubMed2000

Characterization of (125)I-IABN, a novel azabicyclononane benzamide selective for D2-like dopamine receptors.

The properties of an (125)I-labeled structural analog of 2, 3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3. 1]nonan-3beta-yl]benzamide (MABN), (125)I-IABN, are described. (125)I-IABN was developed as a high-affinity radioligand selective for the D2-like (D2, D3, and D4) dopamine receptor subtypes. (125)I-IABN binds with picomolar affinity and nonselectively to rat D2 and D3 dopamine receptors expressed in Sf9 and HEK 293 cells. (125)I-IABN binds with 7- to 25-fold lower affinity to human D4.4 dopamine receptors expressed in HEK 293 cells. Dissociation constants (Kd) calculated from kinetic experiments were in agreement with equilibrium Kd values obtained from saturation binding studies. Saturation plots of the binding of (125)I-IABN with rat caudate membrane preparations were monophasic and exhibited low nonspecific binding. The pharmacologic profile of the binding of (125)I-IABN to rat caudate was consistent with a D2-like receptor, suggesting that the ligand binds primarily to D2 dopamine receptors. In addition, IABN was found to bind with low affinity to D1 dopamine receptors, as well as to the sigma1 and sigma2 receptor subtypes. Quantitative autoradiographic studies using rat brain slices indicate that (125)I-IABN selectively labels the striatum and the olfactory tubercle area, which is consistent with the labeling of D2-like receptors. IABN blocks dopamine-dependent inhibition of adenylyl cyclase activity at D2 or D4.4 receptors expressed in HEK cells. Therefore, (125)I-IABN appears to be a high-affinity, selective antagonist at D2-like dopamine receptors. Finally, a unique property of the azabicyclononane benzamide (125)I-IABN compared to previously studied substituted benzamides is that the binding of this radioligand is not effected by variations in Na(+) concentration.

Animals↗

PubMed1994

Benzamide-induced changes in the actin cytoskeleton in human skin fibroblasts.

The incubation of human skin fibroblasts in the presence of 10 mM benzamide in Joklik's modification of Eagle's Minimal Essential Medium caused an extensive reorganization of actin filaments. The disappearance of stress fibers and changes in cell morphology were observed, whereas no changes in the microtubule architecture were noticed. The observed effects appeared fully reversible within 3 hours after the removal of benzamide. The results are discussed in relation to the two known activities of benzamide as an anaesthetic and an inhibitor of ADP-ribosylation.

Actin Cytoskeleton↗

PubMed1990

The gastrointestinal motor effect of benzamide derivatives is unrelated to 5-HT3 receptor blockade.

The prokinetic properties of a number of 5-HT3 antagonists containing the benzamide moiety (metoclopramide, cisapride, BRL 24924, zacopride) were compared with those of the chemically unrelated antagonist, ICS 205-930. Their 5-HT3 antagonistic potency was evaluated using the Bezold-Jarisch test. All compounds accelerated gastric emptying of beads in the rat, with potencies comparable to those found for inhibiting the Bezold-Jarisch reflex. Metoclopramide, cisapride and zacopride potentiated the twitch contraction of guinea pig ileum and contracted the isolated guinea pig colon in a concentration-dependent manner. Furthermore, they increased the contractility of the gastric Heidenhain pouch in the conscious dog. In contrast, ICS 205-930 was devoid of agonist or antagonist activities in all models except gastric emptying in the rat. Two findings, (1) that benzamide derivatives showed high efficacy in all models of gastrointestinal motility in contrast to ICS 205-930 that was active only to increase gastric emptying, and (2) the different potency order of benzamides in the Bezold-Jarisch test as compared to the in vitro motility tests, indicate that 5-HT3 receptors are involved in gastric emptying, whereas a different receptor operates in the other models used.

Animals↗

PubMed1993

Comparison of the effect of substituted benzamides on midbrain dopamine neurones after treatment of rats for 21 days.

We have tested five different substituted benzamides (nemonapride, D,L-sulpiride, remoxipride, raclopride and zacopride) for their potential to decrease the number of spontaneously active dopamine neurones in the rat midbrain after treatment for 21 days. Nemonapride, D,L-sulpiride, and remoxipride significantly reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, indicating an antipsychotic potential, while raclopride and zacopride induced but minor effects. The number of active dopamine neurones in the substantia nigra pars compacta was reduced by nemonapride at higher doses which should indicate the propensity for developing extrapyramidal side-effects. In conclusion, several of the substituted benzamides showed an antipsychotic profile in this test model. In addition, some of the benzamides also showed a propensity for extrapyramidal side-effects and these results are in accordance with the profile reported from clinical trials. However, the results obtained with this model indicate that raclopride neither has antipsychotic potential nor induces extrapyramidal side-effects. The reason for this discrepancy is at present not known.

Animals↗

PubMed1996

Critical reevaluation of spiperone and benzamide binding to dopamine D2 receptors: evidence for identical binding sites.

There are several inconsistencies in the literature as regards the characteristics of benzamide and butyrophenone binding to dopamine D2-like receptors. The variations observed in Bmax, Kd and Ki values have led to hypotheses, such as the existence of a specific "benzamide binding site' and that dopamine D2 receptors exist in a monomer-dimer equilibrium, where benzamides are supposed to bind receptor monomers and butyrophenones receptor dimers. We have previously suggested that the discrepant results may instead be related to methodological difficulties associated with the use of very high-affinity radioligands (e.g. ligand depletion and failure to achieve equilibrium). The present study was designed to reinvestigate and critically reevaluate the binding characteristics of [3H]spiperone, [3H]nemonapride, [125I](S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6- dimethylsalicylamide ([125I]NCQ-298) and [3H]raclopride to cloned human dopamine D2A and rat striatal dopamine D2 receptors in order to establish whether they label the same receptor population. We found that the Kd values of [3H]spiperone, [125I]NCQ-298 and [3H]nemonapride were about 20 pM and that of [3H]raclopride about 1 nM. We did not find any significant differences between the Bmax values determined with the various radioligands. Furthermore, the Ki values of spiperone and NCQ-298 (derived from cross-competition studies) for dopamine D2 receptors labelled with either [3H]spiperone or [125I]NCQ-298 were in good agreement with the corresponding Kd values. In conclusion, our results clearly demonstrate that when studied under correct experimental conditions, all four radioligands label an identical receptor population.

Animals↗

PubMed1987

Effects of benzamide pretreatment on clastogenic adaptation of Vicia faba root-tip meristem cells to triethylenemelamine (TEM) and maleic hydrazide (MH).

Clastogenic adaptation to TEM or MH no longer occurred when benzamide, an inhibitor of nuclear ADP-ribosyltransferase (ADPRT), was applied prior to the low dose (conditioning) treatment which triggers this phenomenon. This may be indicative that inducible processes connected with ribosylation reactions are involved in the protective effects exerted by clastogenic adaptation. No increase by benzamide pretreatment was observed in the yield of metaphases with TEM- or MH-induced chromatid aberrations after conditioning and challenge treatment, respectively. High benzamide concentrations (1 h, 5 X 10(-3) M) exerted protective effects against TEM challenging but not against MH.

Benzamides↗

PubMed2004

Synthesis and biological evaluation of benzamides and benzamidines: structural requirement of a pyrimidine ring for inhibition of EGFR tyrosine kinase.

The benzamides 1 and the benzamidines 2-3 were synthesized as the mimics of 4-anilinoquinazolines, which possess inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase, and tested for cytotoxicity toward A431 and inhibitory activity toward autophosphorylation by the enzyme assay. High cell growth inhibition was observed in a series of the cyclic benzamides 3: the IC(50) values are 0.09-0.32 mM. The benzamidines 3a and 3b exhibited high inhibition of EGFR tyrosine kinase at a 1.0 microM concentration, although the benzamides 1 and the benzamidines 2 did not show significant kinase inhibition at a 10 microM concentration.

Benzamides↗

PubMed2005

N-(4-{[4-(1H-Benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamide derivatives as small molecule heparanase inhibitors.

A novel class of N-(4-{[4-(1H-benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamides are described as inhibitors of the endo-beta-glucuronidase heparanase. Among them are N-(4-{[4-(1H-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4-methoxy-benzamide (15h), and N-(4-{[5-(1H-benzoimidazol-2-yl)-pyridin-2-ylamino]-methyl}- phenyl)-3-bromo-4-methoxy-benzamide (23) which displayed good heparanase inhibitory activity (IC(50) 0.23-0.29 microM), with the latter showing oral exposure in mice.

Administration, Oral↗

PubMed1984

The in vivo effect of benzamide and phenobarbital on liver enzymes: poly(ADP-ribose) polymerase, cytochrome P-450, styrene oxide hydrolase, cholesterol oxide hydrolase, glutathione S-transferase and UDP-glucuronyl transferase.

Rats fed a synthetic diet containing 0.25% benzamide, 0.1% phenobarbital, separately or in combination, for two weeks showed a significant augmentation in the activity of nuclear poly(ADP-ribose) polymerase as well as changes in various nuclear, microsomal and cytosolic liver enzymes involved in the metabolism of xenobiotics. A selective depression of microsomal styrene oxide hydrolase activity by benzamide feeding, and a contrasting augmentation by phenobarbital, were confirmed by immunological titration of the enzyme-protein content suggesting actual enzyme repression and induction. The NAD content of these livers is not altered significantly as a result of benzamide and phenobarbital feeding, indicating that the changes in enzymes are not a result of non-specific toxic effects.

3-Hydroxysteroid Dehydrogenases↗