Covalent modifications of aminophospholipids by 4-hydroxynonenal.

Lipid oxidation is implicated in a wide range of pathophysiological disorders, which leads to reactive compounds such as aldehydes. Among them 4-hydroxynonenal (4-HNE) reacts strongly with the NH2 groups of amino acids and forms mainly Michael adducts and minor Schiff-base adducts. Such reactions occur also with compounds containing thiol groups. No data are available describing 4-HNE interactions with amino-phospholipids. To investigate such a possibility, 4-HNE was incubated with either phosphatidylethanolamine (PE) or phosphatidylserine (PS) in an aqueous-organic biphasic system and the resulting products were identified by liquid chromatography-mass spectrometry (LC-MS). Our study points out the potential capacity of 4-HNE to react with phospholipids containing amino groups and particularly PE. The main resulting compounds found were a Michael adduct plus a minor Schiff base adduct, which was partly cyclized as a pyrrole derivative via a loss of water. Its stabilization as a pyrrole derivative allows to differentiate 4-HNE from the other aldehydes generated via lipid oxidation (e.g., malondialdehyde, 2-nonenal) that lack the 4-hydroxyl group. Their formation seems not to be affected when the pH varies from 6.5 to 8.5. Surprisingly, PS reacted poorly producing only a small amount of Michael adduct, the Schiff-base adduct being nondetectable. We conclude that such adducts, if they are formed in cell membranes, could alter the phospholipase-dependent cell signaling.

Synthesis and anticonvulsant properties of new benzylpyridazine derivatives.

Several 3-substituted pyridazines and a series of imidazo- and triazolopyridazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures in mice. The most active derivatives, 3-ureidopyridazine 7 and triazolopyridazines 16, 18, 21, and 25 with oral ED50's that ranged from 6.2 to 22.0 mg/kg, were more extensively investigated by evaluating their ability to prevent chemically induced seizures and were compared with phenytoin, phenobarbital, sodium valproate, carbamazepine, and diazepam. 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo-[4,3-b]pyridazine (25) was also protective in the pentylenetetrazole-induced seizures test (ED50 = 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED50 = 34.5 mg/kg per os). Furthermore, derivative 25 showed anticonvulsant effects on bicuculline- and yohimbine-induced seizures tests in mice. All these results suggest that the pharmacological activity of 25 is partly due to modifications of glycinergic and GABAergic transmission. Moreover, molecular modeling studies based on the antiepileptic drug lamotrigine and the most stable conformer of 25 show structural similarities between these two molecules. This conformer also agrees with the electronic tolerances and volume of benzodiazepine pharmacophore models.

A selective inhibitor of thromboxane synthetase activity of rabbit heart tissue: a pyridazinic derivative.

The effects of 2-(2 dimethylaminoethyl) 5-benzylidene 6-methyl (2H,4H)-3-pyridazinone (III) were studied on the biosynthesis of TXA2 and PGI2 in vitro the TXA2 and PGI2 synthetase activity of heart tissue. Biosyntheses of TXA2 and PGI2 were carried out using arachidonic acid as a substrate and horse platelet and aorta microsomes as sources of TXA2 and PGI2 synthetases respectively. TXB2 and 6-keto PGF1 alpha were determined by RIA. III--did not significantly modify either the biosynthesis of PGI2 in vitro or the PGI2 synthetase activity of heart tissue. did not significantly inhibit TXA2 biosynthesis in vitro but markedly reduced the TXA2 synthetase activity of heart tissue: for a microsomal fraction concentration of 100 micrograms protein, the ID50 was 6.37 X 10(-5) M +/- 1.29 X 10(-8) M. Thus III behaves as a specific inhibitor of the TXA2 synthetase activity of heart tissue and could have a beneficial use in therapeutics.

Synthesis of Mannich bases of arylidenepyridazinones as analgesic agents.

A series of 5-arylidenepyridazin-3-ones substituted in the 2-position by an arylpiperazinoalkyl moiety (2-16) was synthesized and evaluated for analgesic activity. In the phenylbenzoquinone-induced writhing test, Mannich bases 2-14 were the most active compounds (6.1 < or = ED50 < or = 43.0 mg/kg, orally; ED50 is the half-maximal effective dose). Pyridazinones 8 and 9, with a 3-chlorophenylpiperazinomethyl substituent, also exhibited significant anti-inflammatory and antipyretic effects. The activities in the phenylbenzoquinone-induced writhing test were subjected to a Hansch analysis, and a significant correlation with lipophilicity and Hammett's constants was obtained.

Behavioural profile of two potential antidepressant pyridazine derivatives including arylpiperazinyl moieties in their structure, in mice.

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PC13), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125.8 and 429.6 mg kg-1. Only at intraperitoneal doses of 100 mg kg-1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5-20 mg kg-1, i.p.) reduced the duration of immobility of mice in the forces swimming test, antagonized reserpine (2.5 mg kg-1, i.p.)-induced ptosis, and potentiated reserpine (2.5 mg kg-1, i.p.)-induced hypothermia. PC4 and PC13 (20 mg kg-1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg-1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg-1, s.c.). At 200 mg kg-1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg-1, s.c.), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg-1, i.p.) in mice pretreated with pargyline (100 mg kg-1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg-1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg-1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (5.0 < ED50 < 5.5 mg kg-1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and aldose reductase inhibitory activity of pyridazine derivatives possessing acetic acid group.

N-acetic acid and S-acetic acid derivatives of 5-arylidene pyridazines were synthesized for evaluation as new aldose reductase inhibitors. Intrinsic activity for each compound was assessed by measuring inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-5) M less than or equal IC50 less than or equal to 10(-4) M). It was found that lipophilicity was important in increasing activity. Furthermore, this activity (log 1/IC50) could be correlated directly to a lipophilic parameter (log kw) for the whole data set.

Synthesis and pharmacological evaluation of 6,8-diaryl 1,2,4-triazolo [4,3,-b] and 1,2,3,4,-tetrazolo [1,5-b] pyridazines.

A series of 6,8-diaryl-1,2,4-triazolo[4,3-b] and 1,2,3,4-tetrazolo[1,5-b]pyridazines was synthesized from suitable chloropyridazines. The compounds were screened in mice for their ability to antagonize maximal electroshock-, pentylenetetrazole- and bicuculline-induced seizures; sedative effects were evaluated by a study of the spontaneous motor activity. Some of pyridazine derivatives exhibited appreciable anticonvulsant activity. Substituting the phenyl ring in the 6-position with an halogen atom led to a substantial increase of activity. Furthermore, none of the compounds was notably active in tests predictive of anxiolytic activity.

[Photobleaching quantum yields of visual pigments in the "fauve de Bourgogne" and "albino" rabbit (author's transl)]. / Rendements quantiques de photodécoloration des pigments visuels du lapin fauve de Bourgogne et du lapin albinos.

Photobleaching quantum yields of visual pigments extracted from retinas of the "fauve de bourgogne" and "albino" rabbit were measured in monochromatic light. For the "fauve de Bourgogne" rabbit, the photobleaching quantum yield was to be 0.65 at different excitation wavelengths (546, 491.6 and 436 nm); at shorter wavelengths, this quantum yield was lower ie. 0.36 at 405 nm. This wavelength effect has been observed on visual pigments extracted from bees retina. In contrast, in the "albino" rabbit, the photobleaching quantum yield was constant and equal to 0.31 whatever the excitation wavelength between 546 and 405 mn.

Synthesis of 6-[(4-imidazol-1-yl)-phenyl]-4-phenyl 4,5-dihydro-2H-pyridazin-3-one: a potential blood platelet aggregation inhibitor.

A new 4,5 diaryl pyridazin-3-one, an analogue of imazodan and Cl-930 was prepared starting from conveniently available chalcone. The resulting derivative was tested in order to determine the area of pharmacological activity. This compound was devoid of positive inotropic effects but showed an important inhibition of PAF-acether induced blood platelet aggregation in vitro with a Cl50 value of 3,4 microM. Ex vivo, anti-aggregating effect against PAF-acether was less important with a DE50 value of 63 mg/kg per os.

[Synthesis and evaluation of the aldose reductase inhibitory activity of new diaryl pyridazine-3-ones]. / Synthèse et évaluation de l'activité inhibitrice d'aldose réductase de nouvelles diaryl pyridazin-3-ones.

It has been possible to prepare from 4,6-diaryl pyridazinones a series of derivatives substituted in the 2-position by chains of various lengths bearing a carboxylic acid function. Pig lens aldose reductase inhibitory activity was evaluated for all compounds. N-acetic acid derivative 3c with a chlorine atom on the phenyl nucleus at the 6-position on the pyridazin ring was the most active pyridazinone with an IC50 value of 1.2 x 10(-5) M. Furthermore, it has been shown that lipophilicity and spatial configuration of the synthesized compounds took a prominent part on enzymatic activity.

Studies on immunostimulating derivatives: synthesis of some pyrrolo[1,2-c]pyrimidines.

In a search for potential immunomodulating agents novel pyrrolo[1,2-c]pyrimidines were synthesized and their structures elucidated by spectroscopic means. Unfortunately, most of them were cytotoxic and devoid of effects on T lymphocyte lymphoblastic transformation. Furthermore, they were inactive in the locomotor activity test in mice.

Anticonvulsant activity of 3-oxo-5-substituted benzylidene-6-methyl-(4H)-2-pyridazinylacetamides and 2-pyridazinylacetylhydrazides.

A series of 3-oxo-5-substituted-benzylidene-6-methyl-(4H)-2- pyridazinylacetamides and 2-pyridazinylacetylhydrazides were synthesized and evaluated for anticonvulsant activity against electrically and chemically induced seizures. In the maximal electroshock-induced seizures test, most of the derivatives showed an anticonvulsant effect better than that of sodium valproate, a commonly used anticonvulsant drug. At 100 mg/kg orally, compounds 5a and 5b respectively protected 50 and 60% of the mice against pentylentetrazole-induced seizures. In addition, these two derivatives showed significant anticonvulsant properties at doses that did not produce ataxia or sedation. The title compounds were also tested for their ability to antagonize convulsions induced by bicuculline and strychnine. Their effect on tremors induced by oxotremorine in mice was also evaluated.

[Synthesis and pharmacologic study of several spirohydantoins: relation to conformation]. / Synthèse et approche pharmacologique de quelques spirohydantoines: relation avec la conformation.

Using two routes starting from cyclanones, it has been possible to prepare two series of spirohydantoins substituted or not on the hydantoin nucleus nitrogen. These compounds exhibited low toxicity on pig lens aldose reductase (except for two compounds). A discussion is given on the steric and geometric requirements for effective enzyme inhibiting activity.

Chemical structure and hemodynamic effects of two new pyridazinone derivatives.

Two new pyridazinone derivatives were selected among two series and assayed for their hemodynamic effects. Their synthesis is described and their chemical structure confirmed by I.R. and N.M.R. data. The 5-arylhydroxymethyl-3-pyridazinone did not induce any significant hemodynamic changes. However, the 5-dichlorobenzylidene-3-pyridazinone, intravenously injected, was active in anesthetized dogs. Moderate doses induced modifications in the heart rate, left ventricular dP/dt max and femoral blood flow and resistance.

[Synthesis and antisecretory and anti-ulcer activity of new 4,6-diarylpyridazinones]. / Synthèse et activités antisécrétoire et antiulcéreuse de nouvelles N-uréidoalkyl pyridazinones.

It has been possible to prepare from 4,6-diaryl pyridazinones a series of derivatives substituted in the 2-position and having urea moiety via the addition of free amines into methylisocyanate. Their gastric anti-secretory and anti-ulcer activities were evaluated. The compounds with an N-2 ethyl chain on the pyridazinone ring (IVa, IVd, IVg) were the most active derivatives.