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PubMed1986

Regional in vivo binding of the substituted benzamide [3H]eticlopride in the rat brain: evidence for selective labelling of dopamine receptors.

The novel substituted benzamide eticlopride, (S)-(-)-5-chloro-3-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxy salicylamide hydrochloride (A38503; FLB 131), was radiolabelled to high specific activity and used for in vivo receptor binding studies in the rat brain. Intravenous injections of [3H]eticlopride resulted in a rapid accumulation of radioactivity in several brain regions: striatum greater than olfactory tubercle greater than septum greater than substantia nigra greater than frontal cortex greater than cerebellum. Approximately 95% of the radioactivity recovered from the striatum was in the form of authentic eticlopride, as determined by thin-layer chromatography. Two hours after injection, the ratio between the amount of radioactivity present in the striatum and in the cerebellum was approximately 10:1. The in vivo binding of [3H]eticlopride was saturable in all dopamine-rich areas, with a very low proportion of non-specific binding. The specific in vivo binding of [3H]eticlopride was blocked by several dopamine antagonists, including haloperidol, (+)-butaclamol, spiperone, d,l-sulpiride and remoxipride. The dopamine agonist N-n-propylnorapomorphine, but not apomorphine, was found to be a potent blocker of in vivo [3H]eticlopride binding. Serotonin and noradrenaline receptor antagonists did not prevent the in vivo binding of [3H]eticlopride. Autoradiographic analysis of the in vivo [3H]eticlopride binding showed a high density of binding sites in the striatum, nucleus accumbens and the olfactory tubercle. Moderate binding was found in the hippocampal formation and in the entorhinal area, but little or no binding was detected in other cortical regions. [3H]Eticlopride binding in all these areas was blocked by pretreatment with (+)-butaclamol. Taken together, these findings show that the substituted benzamide compound [3H]eticlopride passes readily into the brain and binds with high specificity to dopamine or neuroleptic receptors in dopamine-rich brain areas. Thus, eticlopride may be a useful tool in studies of dopamine D-2 receptors in vivo.

Animals↗
PubMed1986

Somatic mutation, DNA damage and cytotoxicity induced by benzo[a]pyrenedione/benzo[a]pyrenediol redox couples in cultured mammalian cells.

BP-3,6-dione was found to be mutagenic, cytotoxic and to induce DNA damage in a transformed line of Syrian hamster fibroblasts at low concentrations, 2 micrograms/ml and less. Inhibition of sulfate and glucuronic acid conjugating enzymes with salicylamide potentiated the above effects of BP-3,6-dione. Diminishing cellular capacity to scavenge superoxide anion radicals also potentiated the mutagenic and cytotoxic action of the dione. The presence of dicumarol, a specific inhibitor of the two-electron reduction of quinones by DT-diaphorase, afforded some protection against cytotoxicity. The results indicate that BP-3,6-dione undergoes two-electron reduction to an unstable hydroquinone, BP-3,6-diol, or one-electron reduction to a semiquinone radical intermediate and that both of these reduced forms undergo rapid univalent oxidation to generate active reduced oxygen species. The data are consistent with the hypothesis that active oxygen species generated by BP-dione/BP-diol redox cycling are responsible, at least in part, for the mutagenic and cytotoxic effects observed with BP-3,6-dione.

Animals↗
PubMed1988

Raclopride, a new selective ligand for the dopamine-D2 receptors.

1. The use of raclopride, a new compound of the salicylamide series, as a ligand for the labelling of dopamine-D2 receptors in vitro and in vivo is described. 2. 3H-Raclopride has a high affinity for the dopamine-D2 receptors (Kd = 1 nM in rat striatum) with much less affinity for any other receptor. 3. 3H-Raclopride enters the brain easily and has therefore also been used in in vivo binding and autoradiography. The nonspecific binding is very low both in vitro and in vivo. 4. Raclopride has been labelled with 11C, and is used as a marker for dopamine-D2 receptors in the living human brain using positron emission tomography.

Animals↗
PubMed1991

Dopamine D2 receptors in the rat, monkey and the post-mortem human hippocampus. An autoradiographic study using the novel D2-selective ligand 125I-NCQ 298.

The distribution of dopamine D2 receptors in the hippocampal region of the rat, monkey and the postmortem human brain was studied with in vitro receptor autoradiography using the selective salicylamide ligand 125I-NCQ 298. Specific binding was defined in the presence of the D2-selective compound raclopride. In all 3 species, higher densities of specifically bound 125I-NCQ 298 was found in the retrohippocampal structures than in the hippocampus proper. In the rat, layers 1 and 3 of the entorhinal cortex and layer 2 of the presubiculum were found to be rich in specific binding sites. In the monkey, the highest densities were detected in the deep layers (4 through 6) of the entorhinal cortex (EC) and in layer 2 of the presubiculum. Relatively high density of binding was found in the granule cell layer of area dentata. In the human brain, less specific binding was seen as compared to the other two species; the highest densities occurred in the outer layers of the presubiculum and in the hilus of area dentata. These findings show that D2 receptors are present in the hippocampal region and that the retrohippocampal region, including the entorhinal cortex, is enriched in dopamine D2 receptors.

Animals↗
PubMed1991

Circadian variation of hepatic UDP-glucuronic acid and the glucuronidation of xenobiotics in mice.

A circadian cycle in hepatic UDP-glucuronic acid (UDP-GA) concentration was observed in mice that was essentially the reverse of those seen for hepatic glycogen and UDP-glucose. That is, hepatic UDP-GA levels were highest during the fasting period and lowest during the feeding period. However, there was no significant difference between the half-lives or the apparent rates of glucuronidation for either acetaminophen or salicylamide at 8 a.m. and 5 p.m. Therefore, the previously-reported circadian variation in acetaminophen toxicity is probably due to circadian variation in hepatic glutathione levels rather than in hepatic glucuronidation capacity.

Acetaminophen↗
PubMed1989

Radiochemical synthesis of [18F]fluororaclopride.

The radiochemical synthesis of [18F]Fluororaclopride (S-3,5-dichloro-6-methoxy-N-(1-(2-[18F]fluoroethyl)-2-pyrrolidinylmet hyl) salicylamide) is accomplished via a two step synthesis. [18F]Fluoroethyltriflate is prepared by [18F]fluoride displacement on the bis triflate of ethylene glycol. [18F]Fluoroethyl triflate is then allowed to alkylate a secondary amine precursor to yield [18F]fluororaclopride. Purification of the radiopharmaceutical involves use of a short silica BONDELUT column and subsequent reverse-phase HPLC. The final product is obtained with a radiochemical yield of approximately 15% (corrected for decay) in a synthesis time of approximately 50 min. Fluororaclopride displays a 3- to 4-fold lower affinity for the D2 receptor than does raclopride.

Fluorine Radioisotopes↗
PubMed1992

Synthesis and evaluation of high affinity, aryl-substituted [18F]fluoropropylbenzamides for dopamine D-2 receptor studies.

The potent dopamine D-2 ligands (S)-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5(3- [18F]fluoropropyl)benzamide (18F-1) and (S)-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3- [18F]fluoropropyl)-6-hydroxybenzamide (18F-2) were prepared in high specific activity and 5-25% overall radiochemical yields. Benzamide 1 possessed a lower in vitro binding affinity for the D-2 receptor than salicylamide 2, but the in vivo striatal-to-cerebellar radioactivity concentration ratios (St/Cb) in rats and dogs were nearly identical for the two compounds. Compound 18F-2 was more lipophilic than 18F-1, and its increased penetration into and retention by striatal tissue was matched by an increase in non-specific binding in the cerebellum. Cerebral cortex radioactivity concentration levels in dogs were similar to cerebellum levels. The binding of 18F-labelled 1 and 2 displayed regional brain distribution patterns consistent with known dopamine D-2 receptor densities and was selectively blocked in the striatum of rats by dopamine D-2 antagonists. The binding of 18F-1 was found to be stereoselective, as the 18F-labelled (R)-enantiomer displayed no selective retention in the striatum of dogs. High levels of radioactivity were found in the bones of rats following the injection of 18F-1 and 18F-2, indicating that in vivo defluorination had occurred; however, no bone radioactivity was observed in dogs following the injection of these radioligands. Compound 18F-1 was displaced from the striatum of dogs by both d-amphetamine-stimulated dopamine release and haloperidol at doses of 1 and 0.5 mg/kg, respectively, while compound 18F-2 was displaced from the dog striatum only by haloperidol at these doses. The radioligand 18F-2 holds promise for positron emission tomography studies of the dopamine D-2 receptor system based upon its selective, potent binding and resistance to displacement by endogenous dopamine.

Animals↗
PubMed2005

Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers.

The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-(p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem's structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC50 values in the range of 4.8-56.0 microM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC50=0.3 microM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.

Animals↗
PubMed2005

The use of colloidal microgels as a (trans)dermal drug delivery system.

A co-polymer of poly(N-isopropylacrylamide) (85%) co-butyl acrylate (10%) co-methacrylic acid (5%) (NIPAM/BA/MAA) (85/10/5) microgel was synthesised and investigated as a potential pH and temperature sensitive transdermal delivery device. Three compounds having different octanol/water partition coefficients and solubilities were incorporated into the microgel, namely: salicylamide (SA), methyl paraben (MP) and propyl paraben (PP). Physico-chemical characterisation of these microgel-drug complexes showed that microgels incorporating MP and SA have smaller volumes after changing environmental pH or temperature when compared with the co-polymer NIPAM/BA/MAA (85/10/5) alone. This reduction in volume could be attributed to the incorporation of the compounds into the microgel particles, having a shielding effect on the charged groups present within the network. Diffusion studies, across human skin, were performed at 305K in the range of pH 3-7 for saturated solutions of SA, MP and PP, and for microgel particles incorporating the three compounds. The transport rate for these microgels incorporating MP was reduced by 2/3-fold compared to the saturated solution, by one order of magnitude for PP, meanwhile the transport rate for these microgels incorporating SA is the same order of magnitude as that for the corresponding saturated solutions. Transdermal release studies of the saturated colloidal dispersions indicated that pH control of the drug release was marginal. The incorporation of compounds into the pH/temperature sensitive co-polymer NIPAM/BA/MAA (85/10/5) and the subsequent release depends on the octanol/water partition coefficient and solubility of the respective compound.

Acrylamides↗
PubMed1991

Inhibition of succinate-ubiquinone reductase by nitrosalicyl-N-alkylamides.

The abilities of eight nitrosalicyl-N-alkylamides to inhibit succinate-ubiquinone reductase were compared. These compounds possess both a nitro group at 3- or 5-position of the benzyl ring, and a methyl, decyl, dodecyl or tetradecyl group subsituted for the amide hydrogen of salicylamide. The result shows the following: (a) 3-Nitrosalicyl-N-alkylamides are stronger inhibitors than 5-nitrosalicyl-N-alkylamides when they have the same alkyl group. (b) The inhibitory abilities of both 3-and 5-nitrosalicyl-N-alkylamides increase with increasing alkyl group length. (c) Kinetic data show that the inhibition by 3-nitrosalicyl-N-tetradecylamide is noncompetitive with respect to the electron acceptor Q2.

Animals↗
PubMed1997

MK-801-induced hyperlocomotion: differential effects of M100907, SDZ PSD 958 and raclopride.

The influence of three selective monoamine receptor antagonists on spontaneous locomotion and on the hyperlocomotion induced by the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801; dizocilpine) was investigated. The selective and potent 5-hydroxytryptamine (5-HT)2A receptor antagonist R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine -methanol (MDL100,907; M100907) displayed a clear-cut selectivity for reduction of MK-801-induced as compared to spontaneous locomotion, in that the former was dose-dependently (0.001, 0.01, 0.1 mg/kg i.p.) blocked and even totally abolished by the highest dose, while the latter was only modestly affected. Even at high doses of M100907 (up to 9 mg/kg i.p.), spontaneous locomotion was not reduced below 40% of control. The selective dopamine D1 receptor antagonist (-)-[4aR, 10 aR]-1,2,3,4,4a,5,10,10a-octahydro-4-(4-chloro-2-methyl-phenyl)-1-methyl- benzo[g]quinoxaline-6-ol (SDZ PSD 958; 0.017, 0.15, 1.35 mg/kg i.p.) decreased both spontaneous and MK-801-induced locomotion with a slight preference for the latter; spontaneous locomotion was dose-dependently diminished to approx. 10% of controls (at 8 mg/kg i.p.). The dopamine D2 receptor antagonist raclopride ([(-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate]; 0.11, 0.33, 1.0 mg/kg i.p.) reduced both MK-801-induced and spontaneous locomotion to a similar extent. An orthogonal matrix experimental design, and multiple regression, were used to evaluate the effects of several combinations of different doses of the 5-HT2A receptor antagonist and the dopamine D1 receptor antagonist. No synergistic actions on reduction of spontaneous or MK-801-induced locomotion were detected between M100907 and SDZ PSD 958. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that the 5-HT2A receptor antagonist M100907 will have efficacy in treating this condition. The lack of effect on spontaneous locomotion, suggests that M100907, compared to dopamine receptor antagonists, will be less prone to induce psychomotor side-effects. Ongoing clinical studies will hopefully give the answers in the near future.

Animals↗
PubMed1999

Release of 5-amino salicylic acid from acrylic type polymeric prodrugs designed for colon-specific drug delivery.

New acrylic type polymeric systems having degradable ester or amide bonds linked to the bioactive agent 5-amino salicylic acid (5-ASA), were prepared and evaluated as materials for colon-specific drug delivery. Methacryloyloxyethyl 5-amino salicylate (MOES), and N-methacryloylaminoethyl 5-amino salicylamide (MAES) were prepared as the polymerizable derivatives of 5-ASA using activated ester methodology. The drug-containing monomers were free radically copolymerized with methacrylic acid or hydroxyethyl methacrylate, utilizing azobisisobutyronitrile as initiator. The polymer bearing 5-ASA units as side substituents of the acrylic backbone were obtained in the form of poly pendent esters or poly pendent amides. The drug release studies were performed by hydrolysis in buffered solutions (pH 1, 7.2, 8.5), or simulated intestinal fluid containing pancreatin to measure the chemical degradation expected to occur in the intestinal tract. The release profiles indicated that the hydrolytic behavior of polymers strongly depends on their degree of swelling, type of comonomer, and the nature of hydrolyzable bond. Implication of the results for use of these polymers for colon targeting are discussed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Relationship between mitochondrial dysfunction and toxicity of propyl gallate in isolated rat hepatocytes.

The relationship between cytotoxicity and mitochondrial dysfunction caused by propyl gallate (PG) has been studied in hepatocytes freshly prepared from fasted rats. Hepatocytes isolated from fasted (18 h) rats were significantly more susceptible to the toxicity of PG than hepatocytes from fed rats. The addition of fructose (15 mM), an alternative carbohydrate source, to hepatocyte suspensions resulted in the prevention of PG (1 mM)-induced cell killing accompanied by decrease in intracellular ATP loss during a 3 h-incubation period. Despite this, fructose did not completely prevent an abrupt loss of intracellular glutathione caused by PG, but effectively inhibited the loss of protein thiol levels. Fructose elicited a concentration (0.5-20mM)-dependent protection against the cytotoxicity of 1.5 mM PG. The incubation of hepatocytes with sodium azide (4 mM), an inhibitor of oxidative phosphorylation, enhanced the toxicity induced by PG (1 mM), but coincubation with fructose delayed the onset of toxicity. Neither azide alone nor fructose plus azide did affect the cell viability during the incubation period. Furthermore, the addition of 2 mM salicylamide, nontoxic to hepatocytes during the incubation period, enhanced PG (1 mM)-induced cytotoxicity and decreased the loss of free PG. These results indicate that the onset of cytotoxicity caused by PG may depend on the intracellular energy status and that mitochondria are critical target for the compound. In addition, the toxicity caused by the inhibition of mitochondrial ATP synthesis is related to the concentration of PG remaining in cell suspensions.

Adenosine Triphosphate↗
PubMed1997

Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors.

Extrastriatal D2-dopamine receptors can be visualised in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [123I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors.

Autoradiography↗
PubMed1985

Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides.

A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.

Animals↗
PubMed2003

Synthesis, anticancer activity, and inhibition of tubulin polymerization by conformationally restricted analogues of lavendustin A.

Compounds in the lavendustin A series have been shown to inhibit both protein-tyrosine kinases (PTKs) and tubulin polymerization. Since certain lavendustin A derivatives can exist in conformations that resemble both the trans-stilbene structure of the PTK inhibitor piceatannol and the cis-stilbene structure of the tubulin polymerization inhibitor combretastatin A-4, the possibility exists that the ratio of the two types of activities of the lavendustins could be influenced through the synthesis of conformationally restricted analogues. Accordingly, the benzylaniline structure of a series of pharmacologically active lavendustin A fragments was replaced by either their cis- or their trans-stilbene relatives, and effects on both inhibition of tubulin polymerization and cytotoxicity in cancer cell cultures were monitored. Both dihydrostilbene and 1,2-diphenylalkyne congeners were also prepared and evaluated biologically. Surprisingly, conformational restriction of the bridge between the two aromatic rings of the lavendustins had no significant effect on biological activity. On the other hand, conversion of the three phenolic hydroxyl groups of the lavendustin A derivatives to their corresponding methyl ethers consistently abolished their ability to inhibit tubulin polymerization and usually decreased cytotoxicity in cancer cell cultures as well, indicating the importance of at least one of the phenolic hydroxyl groups. Further investigation suggested that the phenolic hydroxyl group in the salicylamide ring was required for activity, while the two phenol moieties in the hydroquinone ring could be methylated with retention of activity. Two of the lavendustin A derivatives displayed IC(50) values of 1.4 microM for inhibition of tubulin polymerization, which ranks them among the most potent of the known tubulin polymerization inhibitors.

Antineoplastic Agents↗
PubMed2006

Potent inhibitors of the Qi site of the mitochondrial respiration complex III.

A series of azole-fused salicylamides were prepared as analogues of antimycin and assayed for activity at complex III of the mitochondrial respiratory chain. The activity of these compounds approached that of antimycin in inhibitory potency and some showed growth reduction of Septoria nodorum in vitro. Compound 8a was shown to bind at the Qi site of complex III by red-shift titration of the bc1 complex.

Antimycin A↗
PubMed1983

Fluorescence-microscopic measurement of intracellular cytochrome P-450 enzyme activity (ethoxyresorufin O-de-ethylation) in unfixed liver section.

A fluorescence-microscopic method has been developed for measurement of the intracellular kinetics of the cytochrome P-450 reaction, ethoxyresorufin O-de-ethylation, in individual hepatocytes in unfixed non-frozen liver sections obtained from control or 3-methylcholanthrene-pretreated mice. De-ethylation was enhanced in the presence of salicylamide, but inhibited in the presence of alpha-naphthoflavone, A total of 21 reaction rate curves (fluorescence of the metabolite, resorufin, versus time) were constructed for different individual hepatocytes and groups of two or three hepatocytes, in a total of 12 sections from four control and eight 3-methylcholanthrene-induced mice. No two reaction curves were identical, but the curves were classified, by similarity of curve shape and fluorescence intensity, into three control categories and four 3-methylcholanthrene-induced categories. It was considered that the data represented a total of seven types of hepatocytes, which differed in their ethoxyresorufin de-ethylase reaction characteristics. Hepatocytes in the sections from 3-methylcholanthrene-pretreated mice showed higher de-ethylase activities than the hepatocytes from control mice, but the increase in activity covered a wide range of values, from 3-fold to 17-fold higher than the mean control value, suggesting that 3-methylcholanthrene did not induce ethoxyresorufin de-ethylation to the same extent in all hepatocytes.

Animals↗