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PubMed1994

Catalepsy-associated behavior induced by dopamine D1 receptor antagonists and partial dopamine D1 receptor agonists in squirrel monkeys.

Observational procedures were used to compare the behavioral effects of dopamine D1 receptor antagonists and partial dopamine D1 receptor agonists in squirrel monkeys. The dopamine D1 receptor antagonists SCH 39166 ((-)-trans-6-7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N- methyl-5H-benzo(d)naphtho-(2,1-b)azepine) and BW 737C89 ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7- hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) produced dose-related increases in the duration of static and unusual postures, indicative of catalepsy. R-SKF 38393 (R(+)-7,8- dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine) and SKF 75670 (7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-[1H]-3- benzazepine), which are considered partial dopamine D1 receptor agonists, also consistently produced dose-related increases in catalepsy-associated behavior and had effects comparable in magnitude to those of dopamine D1 receptor antagonists. In contrast, the higher efficacy D1 agonists SKF 81297 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3- benzazepine) and SKF 82958 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine) did not produce catalepsy-associated behavior at any dose tested. The results indicate that dopamine D1 agonists differ with respect to cataleptogenic activity, possibly reflecting differences in intrinsic activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Effects of azelastine on membrane currents in tracheal smooth muscle cells isolated from the guinea-pig.

Azelastine [4-(p-chlorobenzyl)-2-(hexahydro-1-methyl -1H-azepin-4-yl)-1-(2H)-phthalazinone hydrochloride], an anti-allergic agent, inhibited the high K(+)-induced contraction in tracheal smooth muscle cells isolated from the guinea-pig. In order to investigate the ionic mechanisms, we examined the effects of azelastine on membrane currents, using the tight-seal whole cell voltage clamp technique. Azelastine (1-100 microM) caused an inhibition of the Ba2+ inward current (IBa) through the voltage-dependent L-type Ca2+ channel in a concentration-dependent manner. The inhibitory effect of azelastine on IBa was fully reversible. The IC50 value for azelastine-induced inhibition of IBa was approximately 8 microM, and 100 microM azelastine completely suppressed IBa. Azelastine exerted mainly a tonic block of IBa but did not show use dependence. Azelastine (10 microM) shifted the quasi-steady-state inactivation curve of IBa to more negative membrane potentials by approximately -20 mV, suggesting that the inhibitory effect of azelastine on IBa was voltage-dependent. In addition, azelastine produced inhibitory actions on other membrane currents (i.e. the voltage-dependent transient outward K+ current and the Ca(2+)-activated oscillatory K+ current) at doses higher than 10 microM. These results suggest that azelastine inhibits the voltage-dependent L-type Ca2+ current in single tracheal smooth muscle cells, which may contribute to the anti-allergic actions of azelastine in airways.

Animals↗
PubMed1994

Neuroleptics cause stimulation of dopamine D1 receptors and their desensitization after chronic treatment.

Recent evidence indicates that the neuroleptic-induced increase of in vivo acetylcholine output in the striatum does not depend on the relief of cholinergic neurons from the inhibitory control by dopamine, but on increased dopamine output onto dopamine D1 receptors. The present microdialysis study was aimed at finding if the neuroleptic-induced increase in striatal acetylcholine release persists after chronic treatment, and how it is correlated with dopamine output. Rats were chronically treated with the dopamine D2 receptor antagonists, haloperidol and (-)-sulpiride (0.5 mg/kg and 50 mg/kg i.p., respectively, daily, for 30 days). The stimulant effect of both neuroleptics on striatal dopamine release persisted unaltered throughout the chronic treatment (by about 100% over basal values). In contrast, the enhancing effects of haloperidol and (-)-sulpiride on striatal acetylcholine release remained unchanged up to day 12 of treatment. Thereafter, tolerance developed, so that both neuroleptics became totally ineffective on day 30 of treatment. Both on day 1 and 30, the neuroleptic-induced dopamine release was reversed by gamma-butyrolactone (gamma-hydroxybutyric acid lactone), suggesting that this effect is mediated by enhanced neuronal activity. On day 1 and day 10, the neuroleptic-induced acetylcholine release was antagonized by the blockade of dopamine D1 receptors with SCH 39166 (trans-(-)-(6aS,13bR)-11-chloro-6,6a,7,8,9,13b- hexahydro-7-methyl-5H-benzo[d]napht[2,1-b]azepine-12-ol, hydrochloride) (0.5 mg/kg i.p.). SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride) (5 mg/kg i.p.) increased acetylcholine release by about 50% in control rats and in rats treated with (-)-sulpiride or haloperidol for up to 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Enhanced oral activity response to A77636 in neonatal 6-hydroxydopamine-lesioned rats.

To study the role of dopamine D1 receptors in enhanced oral activity effects of SKF 38393 ((+-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) in neonatal 6-hydroxydopamine-lesioned rats, SKF 38393 was compared to the full agonist, A77636 ((1R,3S)-3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy- 1H-2-benzopyran). At 3 days after birth rats were treated with 6-hydroxydopamine HBr (200 micrograms salt form, i.c.v.; desipramine (20 mg/kg i.p.), 1 h) or vehicle. At 6-8 months a 0.01 mg/kg dose of A77636 HCl increased oral activity in 6-hydroxydopamine vs. control rats (P < 0.01). A77636 and SKF 38393 produced identical maximal responses of 35-36 oral movements at 0.1 and 1.0 mg/kg, respectively. SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz azepine ) HCl (0.3 mg/kg i.p.) attenuated the response to A77636. Neither A77636 HCl (0.01-1.0 mg/kg i.p.) nor SKF 38393 HCl (0.03-3.0 mg/kg i.p.) induced oral activity in intact rats. The findings demonstrate that A77636 is more potent than SKF 38393, and that supersensitized dopamine D1 receptors are involved in the induction of oral behavior in neonatal 6-hydroxydopamine-lesioned rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Effect of azelastine on airway hyperresponsiveness mediated by stimulated macrophages.

The effect of the anti-allergic drug azelastine, 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1-(2H)-phth alazione), on airway hyperresponsiveness induced by immunologically stimulated pulmonary alveolar macrophages was investigated in canine bronchial segments under isometric conditions in vitro. Macrophages stimulated with anti-dinitrophenyl immunoglobulin E (IgE) antibody and dinitrophenyl-human serum albumin potentiated the contractile responses to electrical field stimulation at all frequencies, an effect that was abolished by azelastine (3 x 10(-5) M). In contrast, azelastine had no effect on the potentiation of the contractile responses to electrical stimulation by U46619, a thromboxane A2 mimetic. The IgE-mediated release of thromboxane A2 from macrophages was inhibited by azelastine in a concentration-dependent fashion, the maximal decrease and the concentration required to produce a half-maximal effect being 84 +/- 6% (P < 0.001) and 16 microM, respectively. These results suggest that azelastine may attenuate macrophage-induced parasympathetic airway hyperresponsiveness through an inhibition of the release of thromboxane A2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Failure of carbamazepine to prevent behavioural and histopathological sequels of experimentally induced status epilepticus.

Sustained electrical stimulation of the perforant pathway was used to induce long-lasting hippocampal seizures in conscious rats. One hour prior to stimulation, rats were given i.p. injections of either saline or a commonly used antiepileptic drug, carbamazepine (5H-dibenz[b, f]azepine-5-carboxamide; CBZ; 20 mg/kg). When tested 2 weeks later in a water maze, both the saline- and the carbamazepine-pretreated rats showed similarly a severe impairment in spatial learning compared to non-stimulated controls. Histological evaluation revealed that the pyramidal cell damage was (P < 0.05) milder in the carbamazepine-pretreated group in the CA1, but not the CA3c subfield. However, the number of somatostatin-immunoreactive neurons in both stimulated groups was reduced equally. Thus, at the dose of 20 mg/kg, which is a usual anticonvulsive dose in humans, carbamazepine seems to offer only partial protection against pyramidal cell damage, but no protection against the hilar somatostatin-immunoreactive neuron loss or the spatial learning deficit after perforant pathway stimulation in rats. The result clearly differs from that obtained either with a GABA (gamma-aminobutyric acid)-enhancing drug and a novel antiepileptic, vigabatrin (4-amino-hex-5-enoic acid) or with a competitive NMDA (N-methyl-D-aspartate) receptor antagonist, CGP 39551 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid carboxyethylester) in the same test situation.

Animals↗
PubMed1996

Blocking effects of promethazine, triprolidine and their analogues on the excitation caused by the peptide, achatin-I.

An Achatina endogenous tetrapeptide, achatin-I (Gly-D-Phe-Ala-Asp), applied by brief pressure, produced an inward current (Iin) on an Achatina giant neurone type, PON (periodically oscillating neurone). Promethazine, triprolidine and their analogues tested, applied by perfusion, showed a tendency to inhibit the Iin, suggesting that the effective structures vary to a wide extent. With respect to promethazine and its analogues, the presence of 2-bromo, 5-oxo, 3-dimethylsulfamido and 2-methoxy weakened the effects. 10-(2-methylamino-2-methylethyl) instead of 10-(2-dimethylamino-2-methylethyl) of promethazine and the azepine ring instead of phenothiazine ring potentiated the effects. From the dose (pressure duration)-response study of achatin-I, the two promethazine analogues, RP 6497 and RP 6549 (the structures are shown in Fig. 1), inhibited the Iin in partly competitive and partly noncompetitive manners. Regarding triprolidine and its analogues, the compounds in Z-configuration seemed to be more effective than those in E-configuration. The presence of 4-methyl in 1-phenyl, and 1-(4-pyridyl) instead of 1-(2-pyridyl) potentiated the effects. 3-Dimethylamino instead of 3-pyrrolidino weakened the effects. The two triprolidine analogues, Trip Der 3 and Trip Der 6 (the structures in Fig. 2), inhibited the Iin in an uncompetitive manner.

Animals↗
PubMed1988

Involvement of monoamine oxidase and diamine oxidase in the metabolism of the cell differentiating agent hexamethylene bisacetamide (HMBA).

We have previously demonstrated a number of metabolites of hexamethylene bisacetamide (HMBA) in the urine of patients treated with HMBA. These include N-acetyl-1,6-diaminohexane (NADAH), 6-acetamidohexanoic acid (6AcHA), 1,6-diaminohexane (DAH) and 6-aminohexanoic acid (6AmHA). Because these compounds have potential roles in the dose-limiting metabolic acidosis and neurotoxicity associated with HMBA therapy, and are similar in structure to known substrates of monoamine oxidase (MAO) and diamine oxidase (DAO), we investigated the activities of these enzymes in the metabolic interconversion of HMBA metabolites. NADAH (5 mM) was incubated with MAO and aldehyde dehydrogenase. 6AcHA production was verified by gas chromatography-mass spectrometry and quantified by gas chromatography. 6AcHA production was linear for up to 4 hr. Complete inhibition of MAO activity was observed with 2 mM tranyl-cypromine or pargyline. Mouse liver microsomes, which do not contain MAO, did not convert NADAH to 6AcHA and, in control experiments, did not degrade 6AcHA. The HMBA metabolite, DAH, was a substrate for DAO, producing 3,4,5,6-tetrahydro-2H-azepine. Participation of DAO in the metabolism of HMBA implies potential interaction of HMBA and metabolites with polyamine metabolism and may represent a mechanism for HMBA's effects on cellular growth and differentiation. Metabolism of NADAH, also a differentiator, by MAO implies that concurrent use of HMBA and an MAO inhibitor may be clinically useful.

Acetamides↗
PubMed1986

Involvement of extrapyramidal motor mechanisms in the suppression of locomotor activity by antipsychotic drugs: a comparison between the effects produced by pre- and post-synaptic inhibition of dopaminergic neurotransmission.

The effects of two proposed dopaminergic autoreceptor agonists, (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and the azepine derivative B-HT 920, on spontaneous locomotor activity, treadmill locomotion, and catalepsy in the rat have been compared with the effects produced by the postsynaptic dopamine (DA) receptor blocking agent haloperidol. It was found that the threshold dose for suppression of exploratory locomotor activity was 0.5, 0.005 and 0.2 mg/kg for (-)3-PPP, B-HT 920 and haloperidol, respectively. The corresponding doses for suppression of treadmill locomotion were 8.0, 5.12 and 0.2 mg/kg, respectively. Furthermore, (-)3-PPP and B-HT 920, in contrast to haloperidol, did not produce any catalepsy. Thus, using exploratory locomotor activity as an index of limbic forebrain DA functions and treadmill locomotion and catalepsy as indices of extrapyramidal DA functions, the DA autoreceptor agonists, in contrast to the postsynaptic antagonist, show a difference in the doses required to produce these effects. The designation of the behavioral functions as "limbic" or extrapyramidal is supported by the finding that scopolamine, 0.8 mg/kg, antagonized the haloperidol-induced suppression (0.2 mg/kg) of treadmill locomotion, but not the suppression of exploratory locomotor activity.

Adrenergic alpha-Agonists↗
PubMed1993

In vitro and in vivo microdialysis calibration for the measurement of carbamazepine and its metabolites in rat brain tissue using the internal reference technique.

Microdialysis, as in vivo sampling technique, can be used for determining exogenous compounds in the extracellular fluid of freely moving animals and in humans. Usually, calibration of the microdialysis probe is determined by in vitro relative recovery (RR) (dialysate extraction fraction). However, due to different diffusion properties of the compound in tissue, the RR in vivo is different from the RR in vitro. In this study, the evaluation of the internal reference technique as in vivo calibration method was established. To determine the RR in vivo, the relative loss (RL) was defined as the loss of a compound from the perfusate. RL was determined in vitro and in vivo by adding an internal standard (IS) to the perfusate. This internal reference technique was applied for the determination of carbamazepine (CBZ) and its 2 major metabolites, carbamazepine-10,11-epoxide (CBZ-EPO) and trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-DIOL) using 2-methyl-5H-dibenz(b,f)azepine-5-carboxamide (m-CBZ) as IS. In vitro and in vivo, the loss of m-CBZ and the recovery of CBZ are identical. The ratios of the RR of CBZ-EPO and CBZ-DIOL to the RL of m-CBZ are constant, in vitro and in vivo. Therefore, m-CBZ can be used as IS for CBZ, CBZ-EPO and CBZ-DIOL determinations in brain tissue. It is shown that the internal reference technique is a useful method to estimate the true concentration of exogenous compounds in the extracellular space of tissues.

Animals↗
PubMed1992

Determination of the tricyclic compound adosupine and its three metabolites in plasma and brain of rat using high-performance liquid chromatography.

An analytical method for the detection in biological samples of the novel tricyclic compound adosupine (10-acetoamido-5-methyl-5,6-dihydro-11H-dibenzo[b,e]azepin-6 ,11-dione), which is capable of influencing various forms of urinary bladder hyperreflexia has been developed using high-performance liquid chromatography with UV detection. Liquid-liquid extraction was used to isolate the parent compound, three metabolites and an analogue (added as internal standard) from plasma and brain of rat. Adosupine was well separated from its three metabolites with 0.01 M disodium hydrogenphosphate-acetonitrile-methanol-nonylamine (59.986:38:2:0.014) at pH 4.5 as mobile phase using a C18 reversed-phase column. The standard curves were linear in the range 50-5000 ng/ml (or ng/g) for adosupine and metabolites in both plasma and brain. The between- and within-assay variations for high and low concentrations of the parent compound and the three metabolites were 8.2-14%. In the range 50-5000 ng/ml (or ng/g) the accuracy of the method was satisfactory, with the relative error always lower than 10%. Analytical recoveries of added adosupine and the three metabolites were higher than 82%. The method has been applied successfully, to investigate the pharmacokinetics of the drug and its distribution in the central nervous system of rats.

Animals↗
PubMed1992

Automated microanalysis of carbamazepine and its epoxide and trans-diol metabolites in plasma by column liquid chromatography.

A fully automated high-performance liquid chromatographic procedure for the simultaneous determination of carbamazepine and its main metabolites, epoxycarbamazepine and dihydroxycarbamazepine, in plasma is described. Liquid-solid extraction on disposable C18 columns and reversed-phase chromatography on a 3 microns particle size C18 column were combined and automated by using the Automatic Sample Preparation with Extraction Columns system. Ultraviolet detection was performed at 210 nm. 5,6-Dihydro-11-oxo-11H-dibenz[b,e]azepine-5-carboxamide was used as internal standard. A small plasma volume (100 microliters) was required. The total run time for the assay of one sample was about 10 min. The assay demonstrated good reproducibility. The limit of quantitation was 0.1 mumol/l (about 25 ng/ml).

Autoanalysis↗
PubMed1994

Automated microanalysis of oxcarbazepine and its monohydroxy and transdiol metabolites in plasma by liquid chromatography.

An automated high-performance liquid chromatographic method for the simultaneous determination of oxcarbazepine and its monohydroxy and transdiol metabolites in plasma is described. 5,6-Dihydro-11-oxo-11H-dibenz[b,e]azepine-5-carboxamide was used as internal standard. Liquid-solid extraction from plasma (100 microliters) on 50 mg Bond-Elut C18 cartridges was automatically performed by the Automatic Sample Preparation with Extraction Columns (ASPEC) system. A reversed-phase column (ODS Hypersil, 3 microns particle size, 4 cm x 4.6 mm I.D.) was used with acetonitrile-methanol-0.01 M potassium dihydrogenphosphate as mobile phase. The eluted compounds were detected at 210 nm. The limit of quantitation was 0.2 mumol/l for oxcarbazepine and 0.1 mumol/l for its metabolites. No interference with concomitantly administered anti-epileptic drugs such as phenobarbital, phenytoin, valproic acid or carbamazepine, was found.

Anticonvulsants↗
PubMed1993

Kinetic cooperative effect of glycine receptor agonists and antagonists on the dissociation of strychnine binding.

The dissociation of [3H]strychnine binding was studied in synaptosomal membranes of rat spinal cord. Dissociation elicited by 100-fold dilution was accelerated by completely displacing concentrations of glycinergic agents. The rank order of acceleration was iso-THAZ < strychnine approximately taurine < R 5135 < avermectin b1a approximately beta-alanine << glycine (THAZ, 5,6,7,8-tetrahydro-4H-isoxazolo-(3,4-d)azepin-3-ol). The accelerating effects were correlated with the changes of entropy (r = 0.93) but not with the changes of free energies (r = 0.06) of their binding. Half-maximal acceleration was elicited by 58 microM glycine. The accelerating effects of glycine and beta-alanine were attenuated by the antagonists.

Animals↗
PubMed1994

Functional coupling of the human dopamine D3 receptor in a transfected NG 108-15 neuroblastoma-glioma hybrid cell line.

Transfection of a human dopamine D3 receptor cDNA in a neuroblastoma-glioma hybrid cell line (NG 108-15) provided clonal cell lines stably expressing up to 600 fmol per mg protein of [125I]iodosulpiride binding sites. Dopamine and several agonists distinguished two receptor-affinity states in membranes. In the case of dopamine, the high-affinity state (Ki = 0.9 nM, 30% of total binding) was completely converted into a low-affinity state (Ki = 57 nM) in the presence of 10 microM guanosine-5'-O-(3-thiotriphosphate). In addition to these two sites, a site with a very low affinity for dopamine was evidenced in whole cells. The dopamine D3 receptor mediated two responses: c-fos activation, as measured by the appearance of Fos-like immunoreactivity, and increased mitogenesis, as measured by incorporation of [3H]thymidine. The Fos-like immunoreactivity appeared within 30 min, lasted 2 h and was blocked by the partially selective dopamine D3 receptor compound (+)-UH 232 (cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin). The mitogenic effect, which occurred after a lag time (over 2 h stimulation), was produced with subnanomolar potency and full intrinsic activity by several compounds previously identified as dopamine D2 receptor agonists, e.g. quinpirole, (+)-7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and RU 24926 (N-n-propyl-di-beta(3-hydroxyphenyl)-ethylamine), and was reversibly blocked by (+)-UH 232 (Ki = 9 nM). Talipexole (B-HT 920, 5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin) was identified as a partial agonist at the dopamine D3 receptor. Dopamine D3 receptor-mediated mitogenesis was potentiated by a phorbol ester and was abolished by pretreatment with pertussis toxin. A mitogenic effect of same amplitude was elicited by bradykinin or carbachol, both acting through constitutive receptors. Bradykinin markedly activated inositol phosphate turnover, and had no effect on forskolin-stimulated cyclic AMP accumulation. Carbachol inhibited forskolin-stimulated cyclic AMP accumulation and had no effect on inositol-phosphate turnover. Quinpirole had no effect on any of these second messenger pathways. Thus, in transfected NG 108-15 cells, the dopamine D3 receptor is coupled to a pertussis toxin-sensitive G protein and mediates two possibly unrelated biological effects, through initial biochemical events that remain to be identified.

Animals↗
PubMed2005

Two novel series of allocolchicinoids with modified seven membered B-rings: design, synthesis, inhibition of tubulin assembly and cytotoxicity.

Two new attractive series of allocolchicinoids were designed as inhibitors of tubulin assembly using the potent ketone 4 and the tetracyclic, pyrazole annulated NCME variant 7 (NCME = N-acetyl colchinol-O-methylether (2)) as lead structures. The first group of inhibitors of type 6 with novel oxepine and azepine B-ring structures belongs to the NCME-series and was synthesized via a multistep total synthesis starting from simple and cheap 3-methoxybenzaldehyde (12) and 3,4,5-trimethoxybenzaldehyde (13). Biaryl-coupling of the starting materials 12 and 13 was accomplished via Ziegler-Ullmann-reaction to furnish the biphenyl 11 equipped with two carbaldehyde functions. The subsequent Cannizzaro reaction of this dicarbaldehyde 11 proceeded with high regioselectivity to yield almost exclusively the key compound, the hydroxymethyl carboxylic acid 9. Ring closure to the o,o'-bridged biphenyls was accomplished by two routes: on the one hand, treatment of 9 with aqueous hydrochloric acid yielded the lactone 15. On the other hand, a four step sequence starting from the isomeric mixture 9/10 furnished the constitutionally isomeric lactams 23 and 24; these could be converted to the corresponding thiolactams 25 and 26 and to the tetrazole annulated NCME-type derivatives 27 and 28. The second series of bioactive compounds are congeners of allocolchicine (3). The well known desacetyl allocolchicine (29) was easily oxidized to the oxime 30, which was further transformed to the corresponding ketone 31. This served as key precursor for the syntheses of various tetracyclic allocolchicine modifications 33-36 annulated with a pyrazole, isoxazole, pyrimidine or 2-aminopyrimidine heterocycle, respectively. Unexpectedly, all the NCME-variants with a substituent in position 7 like in NCME (2) inhibited the tubulin assembly only moderately. In contrast, the new series of allocolchicine modifications proved to be highly potent antimicrotubule agents. Inhibition of tubulin assembly occurred at lower concentrations compared to those measured for the reference colchicine (1). Surprisingly, these promising results could not be confirmed in the cytotoxicity tests against the human MCF-7 breast cancer cell line, where an unexpected loss of effectiveness compared to the corresponding NCME-derivatives was observed.

Animals↗
PubMed2006

Synthesis of amino acid derived seven-membered lactams by RCM and their evaluation against HIV protease.

A versatile synthesis of hydroxylated and epoxy 1-azepin 2-ones substituted at N1, C-3 and C-4 or C-7 has been developed. The sequence involves ring-closing metathesis of an amino acid derived diene amide, followed by either epoxidation or dihydroxylation, of the resulting alkene. Assay of the product epoxides (10, 18, 25) and diols (9a, 17, 24) against HIV protease reveals micromolar inhibition.

HIV Protease↗
PubMed2006

Capillary and nano-liquid chromatography-tandem mass spectrometry for the quantification of small molecules in microdialysis samples: comparison with microbore dimensions.

Enhanced sensitivity is a well known benefit of miniaturised LC-electrospray (ESI)-MS/MS methods. The suitability of miniaturised LC-MS/MS for quantification of small molecules in dialysates was investigated using the anti-epileptic drug oxcarbazepine, its active metabolite, 10,11-dihydro-10-hydroxycarbamazepine, and the internal standard for microdialysis probe calibration, 2-methyl-5H-dibenz(b,f)azepine-5-carboxamide, as test compounds. ESI-MS detection is sensitive to matrix effects. Therefore, dialysate matrix effects were investigated by comparing the responses of standards made in water, Ringer's solution (salt solution used as perfusion fluid) and blank dialysate matrix. Due to the occurrence of ion suppression or enhancement, direct injection of dialysis samples onto the analytical column could not be applied for quantification of small molecules in dialysis samples. Column switching was necessary for desalting and preconcentration of the dialysates. However, this approach was not able to completely eliminate salt effects when the injection volume exceeded 1 microL. No differences in response between Ringer's solution and dialysate matrix were detected at capillary and nano-dimensions. Calibration standards should be prepared with Ringer's solution instead of water for quantitative analysis of microdialysates. A microbore, capillary and nano-LC-ESI-MS/MS method were compared in terms of method feasibility, linearity, sensitivity, accuracy and precision. Downscaling to capillary and nano-dimensions resulted in a gain in detection sensitivity of 5 and 50, respectively. Miniaturised LC-MS/MS was found to be fit for quantification of small molecules in dialysates with acceptable accuracy and method precision.

Calibration↗