Synthesis, acid-base behavior, and binding properties of 6-modified myo-inositol 1,4,5-tris(phosphate)s.

myo-Inositol 1,4,5-tris(phosphate) was modified at position 6. The analogues synthesized are reported in this publication are 6-deoxy-myo-inositol 1,4,5-tris(phosphate), 6-fluoro-6-deoxy-myo-inositol 1,4,5-tris(phosphate), epi-inositol 1, 4,5-tris(phosphate), and 6-amino-6-deoxy-myo-inositol 1,4, 5-tris(phosphate). These derivatives showed poor affinity for the Ins(1,4,5)P(3) receptors. The inframolecular acid-base behavior and the cooperative effects between the phosphate groups could help explain the loss of affinity of these 6-modified analogues.

Complexation of spermine and spermidine by myo-inositol 1,4,5-tris(phosphate) and related compounds: biological significance.

D myo-inositol 1,4,5-tris(phosphate) (Ins(1,4,5)P3) displays a multicoordination site arrangement that allows strong interactions with polycationic species such as the naturally occurring polyamines spermine and spermidine. In the present work, the complexation of these polyamines by Ins(1,4,5)P3 and related compounds was quantitatively investigated. The study was performed in a 0.1 M tetramethylammonium p-toluenesulfonate (Me4NOTs) solution at 25 degrees C. For purpose of comparison, the complexation of the polyamine-ATP systems were also considered in the same experimental conditions. 31P-NMR experiments showed for Ins(1,4,5)P3 and its analogues, the formation of complexes of a 1:1 stoichiometry. As expected, the most stable complexes are formed between the most charged partners. In addition, the basicity of the phosphate groups seems to govern the stability of the complexes. If both ATP and Ins(1,4,5)P3 are present at the same concentration, the latter interacts preferably with the polyamines. Ins(1,4,5)P3-spermine complex formation provides a possible simple explanation for the inhibition by spermine of Ins(1,4,5)P3-induced Ca2+ release. Spermine will undoubtedly compete with metallic cations such as Ca2+ in the intracellular medium and consequently, may play a regulatory role in the signal transduction mediated by Ins(1,4,5)P3.

Condensation of muscimol or thiomuscimol with aminopyridazines yields GABA-A antagonists.

Ten analogs of muscimol and thiomuscimol in which the amino function was delocalized in an amidinic system were prepared by N2 alkylation of 6-aryl-3-aminopyridazines with (chloromethyl)isoxazole or (chloromethyl)isothiazole derivatives. These muscimol and thiomuscimol derivatives show potent binding properties for GABA-A receptors (they displace [3H]GABA and [3H]gabazine) and provoke convulsions after iv injections. They fit well with the model pharmacophore proposed by our group for the GABA-A antagonists and show similar structure-activity profiles to that of the pyridazinyl-GABAs.

Complexation studies on inositol-phosphates: IV. Ca(II) complexes of myo-inositol 1,4,5-trisphosphate.

The stability constants of the complexes formed between Ca2+ and the myo-inositol 1,4,5-triphosphate (Ins(1,4,5)P3) were determined by potentiometric titration in two different media and temperature conditions (medium 1: I = 0.1 M But4NBr, 25 degrees C; medium 2: I = 0.2 M KCl, 37 degrees C). Mainly because of the presence of potassium the results obtained in these media show large differences in both the nature and the stability of the complexes. In medium 1, MH2L and M2L species are formed along with the ML and MHL species which also exist in medium 2. In addition, the stability of the latter species decreases by more than one log unit in going from medium 1 to medium 2. In an attempt to assess the biological significance of the metal binding to Ins(1,4,5)P3, the results were compared to the Ca2+-ATP complexes that form in the same media conditions. Taking into account the relative stability of the complexes of both systems, it is likely that the action or metabolism of Ins(1,4,5)P3 may be influenced by coordination of either alkali or alkali-earth cations.

Ionization state of myo-inositol 1,4,5-trisphosphate: correlation with binding properties.

The comparison between the ionization state and the binding properties on brain membrane receptors of the synthetized myo-inositol 1,4,5-trisphosphate lead to the conclusion that the biological active species may be either the monoprotonated or the fully deprotonated trisphosphate.

GABA-uptake inhibitors: construction of a general pharmacophore model and successful prediction of a new representative.

A model for the pharmacophore of GABA-uptake inhibitors was established using published structure-activity data and molecular modeling. The model accounted for the activities of different classes of GABA-uptake inhibitors. Analogues of guvacine substituted at position 6 were synthesized in order to confirm the model. 6-(3,3-Di-phenylpropyl)guvacine (30f), which fit well with the pharmacophore, had an in vitro IC50 of 0.1 microM. This value is as good as those of the best GABA-uptake inhibitors known today.

Complexation studies on inositol-phosphates. II. Alkali-metal complexes of D-myo-inositol 1,2,6 trisphosphate.

The complexation properties of the D-myo-inositol 1,2,6 trisphosphate (Ins(1,2,6)P3) towards Li+, Na+, K+, Rb+, and Cs+ cations were studied at 25 degrees C in a 0.1 M tetra-n-butylammonium bromide medium. For all cations, mononuclear and protonated species were found. For smaller cations (Li+, Na+, and K+) a dinuclear complex was also put into evidence. The main characteristic of the complexes is its high stability; and of the ligand, its nonselectivity. The Ins(1,2,6)P3-K system was ascertained using Sammartano's method which additionally enabled the influence of various K+ concentrations on the protonations constants to be considered.

3-aminopyridazine derivatives with atypical antidepressant, serotonergic, and dopaminergic activities.

Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring.

The sensitivity of gamma-aminobutyric acid antagonists to thiocyanate is related to the absence of a functional anionic group in their structure.

Pyridazinyl derivatives of gamma-aminobutyric acid (GABA) have recently been shown to be selective, reversible and competitive GABAA antagonists. Unlike what is observed with all other GABAA antagonists, the affinity of these compounds for the GABAA receptor is not modified by thiocyanate. The chemical structure of these pyridazinyl-GABA derivatives differs from that of other GABAA antagonists by the presence of a free carboxylic group in their structure. We speculated that this could explain their lack of sensitivity to thiocyanate. Consequently, we synthesized three structural analogues of these pyridazinyl-GABA derivatives in which we replaced the free carboxyl group by a cyano group. These compounds displaced [3H]GABA from rat brain membranes and reversed the GABA-induced enhancement of [3H]diazepam binding. However their affinity for the GABAA receptor increased 10- to 20-fold in the presence of thiocyanate. Thus, sensitivity to thiocyanate appears to be related more to the absence of an anionic functional group than to the agonist or antagonist nature of the GABAA ligand.

Synthesis and structure-activity relationships of a series of aminopyridazine derivatives of gamma-aminobutyric acid acting as selective GABA-A antagonists.

We have recently shown that an arylaminopyridazine derivative of GABA, SR 95103 [2-(3-carboxypropyl)-3-amino-4-methyl-6-phenylpyridazinium chloride], is a selective and competitive GABA-A receptor antagonist. In order to further explore the structural requirements for GABA receptor affinity, we synthesized a series of 38 compounds by attaching various pyridazinic structures to GABA or GABA-like side chains. Most of the compounds displaced [3H]GABA from rat brain membranes. All the active compounds antagonized the GABA-elicited enhancement of [3H]diazepam binding, strongly suggesting that all these compounds are GABA-A receptor antagonists. None of the compounds that displaced [3H]GABA from rat brain membranes interacted with other GABA recognition sites (GABA-B receptor, GABA uptake binding site, glutamate decarboxylase, GABA-transaminase). They did not interact with the Cl- ionophore associated with the GABA-A receptor and did not interact with the benzodiazepine, strychnine, and glutamate binding sites. Thus, these compounds appear to be specific GABA-A receptor antagonists. In terms of structure-activity, it can be concluded that a GABA moiety bearing a positive charge is necessary for optimal GABA-A receptor recognition. Additional binding sites are tolerated only if they are part of a charge-delocalized amidinic or guanidinic system. If this delocalization is achieved by linking a butyric acid moiety to the N(2) nitrogen of a 3-aminopyridazine, GABA-antagonistic character is produced. The highest potency (approximately equal to 250 times bicuculline) was observed when an aromatic pi system, bearing electron-donating substituents, was present on the 6-position of the pyridazine ring.

Allergic contact dermatitis to methylenelactones. Use of lymphocyte transformation test.

Seventeen guinea pigs were sensitized to alantolactone, a natural sesquiterpene lactone known for its sensitizing properties, using intradermal injections in Freund's complete adjuvant. Guinea pig skin protein extracts (SPE) were used to make conjugates with alantolactone and an isomer, isoalantolactone. Lymphocyte blastogenesis was observed with SPE-alantolactone conjugates, as well as with guinea pig albumin-lactone conjugates. In six cases, stimulation was noted with unconjugated haptens. These results do not show a high degree of hapten-carrier specificity in contact sensitivity to alantolactone, induced by unconjugated hapten injections. Cross-sensitivity with SPE-isoalantolactone conjugate was also observed.

Synthesis of alpha-methylene-gamma-butyrolactones: a structure-activity relationship study of their allergenic power.

Thirty-five alpha-methylene-gamma-butyrolactones have been prepared and their allergenic properties tested on the skin of guinea pigs experimentally sensitized to (a) alantolactone (1), (b) isoalantolactone (2), and (c) alpha-methylene-gamma-butyrolactone (3). The two first groups of animals cross-react to lactones containing 9 to 18 carbon atoms but not to smaller alpha-methylene-gamma-butyrolactones. Conversely, animals sensitized to alpha-methylene-gamma-butyrolactone react only with alpha-methylene-gamma-butyrolactones containing 6 and 7 carbon atoms. These results are discussed in relation with the allergic contact dermatitis mechanism.

[Allergologic studies of intolerance to rosin]. / Etude allergologique d'intolérances à la colophane.

Patch-tests made in 13 persons who were allergic to colophony revealed quite different allergologic profiles. Some patients reacted only to abietylic alcohol while others did not react to abietic acid. Methylabietate used as plasticizer in sticking-plasters and especially "hypoallergic" ones, had an allergizing effect in 6 out of 12 cases.

[Allergy to rosin caused by patch tests]. / Allergie à la colophane des patch-tests.

5 commercial patch-test-products were investigated by gas chromatography. Colophony was detected in three of the products, and the allergen was found in the adhesive component.

Eczemas due to plant allergens in manufactured products.

Intolerance to plant allergens in manufactured products is widespread. Results of epidemiological investigations in STRASBOURG are given. The rate of allergy to sesquiterpenic lactones has fallen since 1974, due to the fact that the use of an ointment containing these lactones has decreased. Disguised forms of allergens are reviewed, for instance limonene of Niaouli oil (Biogaze), colophony of "hypoallergenic" tapes or of testing material. Chemical investigations are useful in prevention and in allergological control of medicaments.

[Investigation of the allergens of colophony and its derivatives used in the manufacture of sticking-plasters (author's transl)]. / Etude des allergènes de type colophane et dérivés, utilisés dans des sparadraps.

Colophony and its derivatives play an important part in intolerances to sticking-plasters. Gas chromatography revealed resinic acids (derivatives) in numerous products of that kind, even in the so-called "hypoallergic" ones. The profiles of the resinic acids contained in some sticking-plasters that are sold in several countries under identic names, are rather different. The results of physicochemical analysis of Elastoplaste, the normal French product, and of a "hypoallergic" product, coincide with the results of allergologic studies.

Allergic contact dermatitis due to sesquiterpene lactones. A comparative study of human and animal sensitivity to alpha-methylene-gamma-butyrolactone and derivatives.

Several compounds containing the alpha-methylene-gamma-butyrolactone moiety have been tested on human volunteers and on guinea-pigs; the animals were experimentally sensitized by alantolactone, isoalantolactone and laurel oil. Of the two new lactones, spirolactone was the more reactive: this was confirmed by both animal and human testing. The synthetic lactones are less reactive than natural ones. alpha-Methylene-gamma-butyrolactone itself does not elicit cross-reactions in guinea pigs sensitive either to alantolactone or to isoalantolactone, or in patients sensitive to sesquiterpene lactones. The alpha-methylene-gamma-butyrolactone group is necessary for cross-reaction, but to be active, it has first to be substituted. It was also found that isoalantolactone, allegedly not allergenic, is in fact a sensitizer and cross-reacts with alantolactone. The cross-reaction between laurel and Frullania, found in man, also occurs in guinea-pigs. It is more evident when sesquiterpene lactone is the sensitizer and laurel used to elicit reaction.