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PubMed1992

Synthesis and evaluation of iodinated benzamide derivatives as selective and reversible monoamine oxidase B inhibitors.

A new series of iodinated analogues of N-(2-aminoethyl)benzamide was synthesized and evaluated for inhibitory potency and specificity toward monoamine oxidase type-B (MAO-B). Among them, N-(2-aminoethyl)-2-chloro-4-iodobenzamide hydrochloride (2d) showed high inhibitory potency and selectivity against MAO-B. The type of MAO-B inhibition by 2d was non-competitive and the inhibition constant (Ki) was 0.80 microM. Strong and selective in vivo MAO-B inhibition by 2d was also confirmed. The brain MAO-B inhibition by 2d was reversible and the enzyme activity completely returned to the control value 24 h after administration. Compound 2d was, therefore, considered to be a candidate for advanced development as a radioiodinated ligand that may be useful for functional MAO-B studies in the living brain using single photon emission computer tomography.

Animals↗
PubMed1992

Synthesis, gastrointestinal prokinetic activity and structure-activity relationships of novel N-[[2-(dialkylamino)ethoxy]benzyl]benzamide derivatives.

Novel N-[[dialkylamino)ethoxy]benzyl]benzamide derivatives (II-1-51), derived from the structural modification of metoclopramide (I), were synthesized and examined for their pharmacological activities. Among them, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide (II-34) which exhibited well balanced gastrointestinal prokinetic and antiemetic activities was selected as a new type of gastrointestinal prokinetic agent.

Amines↗
PubMed1994

Synthesis and biological activities of the optical isomers of (+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl]benzamide (mosapride).

The enantiomers, (S)-(-)-1 and (R)-(+)-1, of (+/-)-4-amino-5-chloro-2-ethoxy- N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride) [(+/-)-1], a new and selective gastroprokinetic agent, were prepared from optically active [4-(4-fluorobenzyl)-2-morpholinyl]methylamines (S)-(-)-4 and (R)-(+)-4, respectively. The requisite (S)-(-)-4 and (R)-(+)-4 were prepared by optical resolution of [4-(4-fluorobenzyl)-2-morpholinyl]methyl p-toluenesulfonate [(+/-)-5] using (-)- and (+)-N-(p-toluenesulfonyl)glutamic acids, followed by amination of the tosyloxy groups of (R)-(-)-5 and (S)-(+)-5, respectively. The absolute configurations of (R)-(-)-5 and (S)-(+)-5 were determined on the basis of an asymmetric synthesis of (R)-(-)-5 from (S)-(+)-benzyl glycidyl ether [(S)-(+)-11]. Mosapride and its enantiomers, (S)-(-)-1 and (R)-(+)-1, were essentially equipotent in serotonin 5-HT4 receptor agonistic activity on the electrically evoked contractions in isolated guinea pig ileum.

Animals↗
PubMed1998

Synthesis and structure-activity relationship of 3-Substituted benzamide, benzo [b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-77-carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5-HT4 receptor agonists.

The title compounds (6-9) were prepared and evaluated for serotonin 5-HT4 agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b]furan skeleton and 2,3-dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2-methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dimethylbenzo[b]furan-7-carboxamide (8d) hemifumarate were more potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D1, D2, serotonin 5-HT1, 5-HT2 and muscarine M1, M2 receptor binding activity in the in in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.

Animals↗
PubMed2000

Preparation and characterization of two crystalline forms of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrroli dinyl]benzamide (TKS159).

For 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolid inyl]benzamide (TKS159), two polymorphs, forms alpha and beta, were prepared and characterized by means of X-ray powder diffractometry, thermal analysis, infrared spectroscopy and 13C-NMR spectroscopy, both in the solution and solid phases. The X-ray powder diffraction analysis gave different patterns for forms alpha and beta. In the thermogravimetry and differential thermal analysis profiles, form beta exhibited characteristic endo- and exothermic peaks at 112.7 degrees C and 116.2 degrees C, respectively, due to the partial melting-induced phase transition to form alpha without accompanying weight loss, and these were followed by an additional endothermic peak at 138.2 degrees C due to fusion. For form alpha, only an endothermic peak at 137.8 degrees C due to fusion was observed. The IR spectroscopic analyses of forms alpha and beta gave different absorption bands assigned to N-H and O-H stretching, N-H bending, and C=O stretching vibrations. From the data obtained by thermal analysis, form alpha was shown to be thermodynamically more stable than form beta.

Benzamides↗
PubMed2001

Synthesis and gastrointestinal prokinetic activity of novel benzamide derivatives with amphoteric side chains.

Novel benzamide derivatives (19-24, 32a-c, 43d-f), each possessing a cycloaminoalkanecarboxylic acid side chain, were synthesized and their gastrointestinal prokinetic and dopamine D2 receptor antagonist activities were evaluated. 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (19) exhibited the most potent gastro- and colon-prokinetic activities, through intravenous administration to conscious dogs, and also showed the reduced dopamine D2 receptor antagonistic activity. However, 19 showed only weak gastrointestinal prokinetic activity after oral administration. Several ester prodrugs (44-62) of 19 were tested for pharmacological activities as well as physicochemical and metabolic stability; the butyl ester (46) was consequently selected as a promising gastrointestinal prokinetic agent with reduced side effects.

Animals↗
PubMed1996

Gastroprokinetic effect of a new benzamide derivative itopride and its action mechanisms in conscious dogs.

The novel benzamide derivative itopride was assayed for its effect on gastrointestinal motility in conscious dogs when it was administered intraduodenally (i.d.). Gastrointestinal motility was measured by means of chronically implanted force transducers, and itopride at a dose of 10 mg/kg, i.d. or more increased the gastric contractile force during the digestive state. Intraduodenal cisapride, domperidone and metoclopramide also stimulated gastric motility, and their threshold doses were 1, 3 and 1 mg/kg, respectively. Dopamine infusion (1 mg/kg/hr, i.v.) caused the postprandial gastric motility to disappear, but it was immediately restored by itopride at a dose of 3 mg/kg, i.d. With itopride at 1 and 3 mg/kg, i.d., acetylcholine (0.05 mg/kg/min)-induced contractions were greatly enhanced. In addition to its gastric stimulation, itopride at doses of 10-100 mg/kg, p.o. inhibited apomorphine (0.1 mg/kg, s.c.)-induced vomiting in dogs. In conclusion, intraduodenal itopride stimulates gastric motility through both anti-dopaminergic and anti-acetylcholinesterase actions. Its gastroprokinetic threshold dose was as large as 3-10 times those of cisapride, domperidone and metoclopramide. These findings suggest that itopride is an orally active gastroprokinetic with a moderate anti-emetic action.

Animals↗
PubMed1993

Effects of benzamide derivatives on dopamine release from striatal slices of rats.

The effects of the benzamide derivatives, (-)-sulpiride, sultopride and nemonapride, on spontaneous and electrically evoked dopamine (DA) release from striatal slices of rats were investigated. Nemonapride at concentrations of 100 nM or higher caused a dose-dependent increase in spontaneous DA release from the slices. (-)-Sulpiride and sultopride had little effect on spontaneous DA release. The electrically evoked DA release was enhanced by (-)-sulpiride at concentrations of 100 nM or higher in the superfusate and reduced by nemonapride at 100 nM or higher. Sultopride caused a small increase in the evoked release of DA. The different activities of these drugs on DA release may account for the different clinical results they produce.

Amisulpride↗
PubMed1992

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Benzamides↗
PubMedDate not supplied

Synthesis of 4-(acylaminomethyl)benzamides and their evaluation as potential anticancer agents.

4-(acylaminomethyl)benzamides were prepared in two steps from 4-aminomethylbenzoic acid and assayed in the NCl's primary anti-cancer screen. Eight out of 34 compounds showed interesting antiproliferative activity. From these compounds, three were selected for further in vivo testing. In addition, all the compounds were tested against farnesyltransferase and the cell cycle regulating enzymes cdc2 kinase and cdc25 phosphatase. The compounds proved inactive in these assays, as were some selected compounds in an assay searching for possible interference with the ras/raf interaction in a yeast two-hybrid system.

Alkyl and Aryl Transferases↗
PubMed1975

[A new substituted benzamide with neuroleptic effects: lin 14 18 or sultopride].

After the research about Sulpiride, a new substituted benzamide has been studied. Although it was characterized by modest pharmacological effects in the neuroleptic identification tests, LIN 1418 turned out to have very interesting therapeutic properties. A study conducted with 50 cases, 30 of which were submitted a systematic pluridisciplinary control, leads to provisory conclusions as follows: 1) its psychotropic effects are powerful and constant; 2) its prevailing action is antipsychotic and desinhibiting altogether; 3) while LIN 1418 appears as successful with all psychoses, whether acute or chronic, up to now, the quality of its results in many chronic psychoses seems to be particularly remarkable; 4) its side-effects are those of most neuroleptics: its extrapyramidal symptoms being all the more obvious as the patient's "passivity" is less important.

Adult↗
PubMed1998

[Synthesis and vasodilative activities of benzamide derivatives].

Twenty two benzamide derivatives were synthesized of which twenty one were not reported before. Vasodilative activity screening in vitro has shown that most of the compounds possess various activities, among which compound H1, H11, H17, E1, E3 demonstrated a superior pharmacological profile to the lead compound when inhibiting effect on the noradrenaline (10(-7) mol.L-1) induced contraction of rat aortic strip was chosen as the evaluation criterion, while H7,15, E7 exerted significant inhibiting action toward 85.7 mmol.L-1 KCl induced contraction of rat aortic strip. Further evaluation assays for their KCO potentials showed that E1 might be an ATP sensitive KCO. Preliminary structure-activity relationships of this kind of aromatic amides are discussed herein.

Animals↗
PubMed2003

Modulation of histone acetylation by [4-(acetylamino)-N-(2-amino-phenyl) benzamide] in HCT-8 colon carcinoma.

CI-994 or N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] is an antitumor cytostatic agent currently undergoing clinical trial. Although several changes in cellular metabolism induced by the drug have been characterized, the primary molecular mechanism of its antitumor activity has been previously unknown. Here, we show that CI-994 is a histone deacetylase (HDAC) inhibitor that causes histone hyperacetylation in living cells. In assays of isolated enzymes, CI-994 inhibited HDAC-1 and HDAC-2 in a concentration-dependent fashion but had no effect on the activity of the prototypical histone acetyltransferase GCN5. Acetylated histone H3-specific Western blots were used to monitor histone acetylation in HCT-8 colon carcinoma cells treated with CI-994 in vitro. CI-994 induced hyperacetylation of H3 in a time- and dose-dependent fashion. H3 hyperacetylation was detectable as early as 30 min after the addition of CI-994 to cells. These data demonstrate that inhibition of HDAC is an early event in cells treated with CI-994 and suggest that this inhibition is mechanistically related to the antitumor activity of this compound.

Acetylation↗
PubMed1990

Sodium-dependent isomerization of dopamine D-2 receptors characterized using [125I]epidepride, a high-affinity substituted benzamide ligand.

We have characterized the in vitro binding of a new ligand, [125I]epidepride, and used this substituted benzamide to assess the sensitivity of dopamine D-2 receptors to sodium. Both direct and indirect binding studies with [125I]epidepride and unlabeled epidepride, respectively, demonstrated that the affinity of D-2 receptors for the ligand was decreased from 20 to 30 pM in the presence of sodium to 350 to 500 pM in the absence of sodium. The density of binding sites for [125I]epidepride was identical in the presence and absence of NaCl. The time courses for association of [125I]epidepride to and dissociation from D-2 receptors in the presence of sodium were not consistent with simple bimolecular reactions, suggesting the possibility of a sodium-dependent ligand-induced receptor isomerization. Thus, dissociation of [125I]epidepride was biphasic in the presence of sodium, but monophasic in the absence of sodium. The rank order of potency for inhibition of [125I]epidepride binding by drugs was identical in rat striatum and cells expressing a D-2 receptor cDNA, and similar to the previously described pharmacological profile of D-2 receptors labeled by [3H]spiperone. [125I]Epidepride bound to two classes of binding sites in rat medial prefrontal cortex. One class, present at a density of 10 fmol/mg of protein and with a Kd value of approximately 40 pM, was pharmacologically indistinguishable from D-2 receptors in striatum and transfected cells. The pharmacological profile of the second class of sites was similar to that of alpha-2 adrenergic receptors. [125I]Epidepride had 50- to 100-fold lower affinity (approximately 2 nM) for alpha-2 receptors than for D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Metabolism and disposition of (R)-4-[3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl]benzamide Hcl (LY 195448) in rodents.

The disposition and metabolism of (R)-4-[3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl]benzamide HCl, or LY 195448 (LY), were studied in rodents 1 hr following a single iv injection of 14C-LY at 30 mg/m2 (10 mg/kg mice and 5 mg/kg rats), In all tissues and carcases, recovery of 14C was nearly complete. The majority of radioactivity was recovered from intestine (40%) whereas liver and urine accounted for 10% each, kidney for 3-5%, and plasma for 1-3% of total administered radioactivity. Analyzing by HPLC and TLC, para-hydroxy-LY (para-OH-LY) in addition to unchanged drug, was found in all tissues. Meta-OH-LY was detected only in urine, intestine and kidney. These metabolites were found to be conjugated with either glucuronide or sulfate moieties. Peaks coeluting with authentic para-OH-meta-methoxy-LY and di-OH-LY were also observed.

Animals↗
PubMed1988

[Effects of an anti-inflammatory agent of benzamide structure, dexamethasone and indomethacin on experimental cerebral edema induced by phospholipase 2 in rats].

Only a few molecules show any efficacy against brain edema. Different methods such as brain copper-wire implantation or arachidonic acid injection are used in the research of active drugs. A new model, involving injection of phospholipase A2, is described. The effect of an anti-inflammatory compound, N-(4,6-dimethyl 2-pyridinyl) benzamide, was evaluated on the three different experimental brain edemas mentioned above; dexamethasone and indomethacin were used as reference drugs. The studied molecule is, like dexamethasone, active on the three brain edema models. It has no direct inhibitory effect on phospholipase A2, cannot block cyclooxygenase activity but does reduce prostaglandin biosynthesis. Other factors, such as dopaminergic and alpha 2-adrenergic agonist activities, could also interfere.

Animals↗