Respective contributions of alpha-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs.

The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central alpha2-adrenoceptors (alpha2ARs). However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline-like drugs with no alpha2-adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an alpha2ARs agonist alpha-methylnoradrenaline (alpha-MNA). We selected S23515 and S23757, two imidazoline-like drugs with negligible affinities and activities at alpha2ARs but with high affinities for non-adrenergic imidazoline binding sites (IBS). S23515 decreased BP dose-dependently (-27+/-5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 microg kg(-1) i.c.) was prevented by S23757 (1 mg kg(-1) i.c.) and efaroxan (10 microg kg(-1) i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of alpha-MNA (3 and 30 microg kg(-1) i.c.). Moreover, the alpha2ARs antagonist rauwolscine (3 microg kg(-1) i.c.) did not prevent the effect of S23515. Finally, whilst 3 microg kg(-1) of S23515 or 0.5 microg kg(-1) of alpha-MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (-23+/-2%). These results indicate that an imidazoline-like drug with no alpha2-adrenergic properties lowers BP and interacts synergistically with an alpha(ARs agonist.

Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands.

Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I1 and I2) and alpha-adrenergic (alpha1 and alpha2) receptor ligands. Their pKi values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases alpha-adrenergic affinity. I1 sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(2'-methoxyphenyl)-imidazoline (17) is one of the best I1 ligands ever reported (pKi = 8.53 and I1/I2 > 3388). On the other hand, I2 selectivity increases in the presence of a methyl group in the para position. The original compound, 2-(3'-fluoro-4'-tolyl)-imidazoline (31) is a new potent ligand for the I2 sites with high selectivity (pKi = 8.53 and I2/I1 > 3388).

[Synthesis and antidepressive activity study of aryl and heteroaryl carboxamides of benzylpiperazine]. / Synthèse et étude de l'activité antidépressive d'aryl et hétéroaryl carboxamides de la benzylpipérazine.

The synthesis of 44 original amide derivatives of benzylpiperazine and some analogues of befuraline and piberaline is reported. All compounds have been tested as antidepressive agents. According to the tests, amides 1, 24 and mainly 31 (dihydrobefuraline) seem to provide elevated antidepressive activity.

3D-QSAR CoMFA study on imidazolinergic I(2) ligands: a significant model through a combined exploration of structural diversity and methodology.

Displaying an unprecedented structural diversity, 119 I(2) ligands, and their pK(i) values, were collected and submitted to a comparative molecular fields analysis (CoMFA) study. They were discerned into three structural subsets (A, B, C), to explore the I(2) 3D-QSARs from finite structural systems (A, B, C) to more complex ones (AB, AC, BC, ABC). In addition, various key steps of the CoMFA methology were explored. The applied method used two pharmacophore templates and seven molecular field combinations (electrostatic, lipophilic, steric), as well as eight alignment methods (two point-by-point and six similarity-based variations). That way, 644 CoMFA models were obtained and further selected according to their predictive ability through two filters. The first filter was mainly based on the q(2), which internally evaluates the predictive ability from the training set. For the second filter, the predictive ability was externally evaluated through the prediction of test sets. Finally, one model was extracted from the whole data as the best. Indeed, it combines three features of upmost importance for the further design of ligands endowed with high I(2) affinity: structural diversity (n = 73), robustness (N = 9, r(2) = 0.96, s = 0. 28, F = 148), and a great fully assessed predictive ability (q(2) = 0.50, r(2)(test set) = 0.81, n(test set) = 46). On the basis of structural data and CoMFA isocontours, some elements of the I(2) tridimensional pharmacophore are also suggested.

Synthesis and structure-activity relationships of novel arylalkyl 4-benzyl piperazine derivatives as sigma site selective ligands.

Continuing our previous work that established that some chromones substituted by an aryl alkyl piperazino alkyl side chain are potent and selective sigma ligands and could be interesting in the treatment of psychosis, we synthesized 60 new compounds, replacing the chromone moiety by various cyclic systems. Many derivatives bind to the sigma sites in the nanomolar range and are generally selective in comparison with 5HT(1A) and the D(2) receptors. One of the most potent ligands of these series, 1-(2-naphthyl methyl)-4-benzyl piperazine 29, has been studied in various pharmacological tests. Although it doesn't have potential in the treatment of psychosis, the results we obtained confirm the data which indicates that such derivatives could be interesting in the treatment of inflammatory diseases.

Antipoliovirus structure-activity relationships of some aporphine alkaloids.

A series of 18 aporphinoids have been tested in vitro against human poliovirus. The aporphines (+)-glaucine fumarate (1), (+)-N-methyllaurotetanine (4), (+)-isoboldine (7), and (-)-nuciferine, HCl (10) were found to be active with selectivity indices > 14. The nature of the 1, 2-substituents of the isoquinoline moiety appeared to be critical for antipoliovirus activity. An SAR study demonstrated the importance of a methoxyl group at C-2 on the tetrahydroisoquinoline ring for the induction of antipoliovirus activity. Molecular modeling of some compounds in this series revealed the close similarities between the three-dimensional conformational features of the inactive 1,2-substituted derivatives (+)-boldine (6) and (+)-laurolitsine (5) with derivatives containing the 1,2-(methylenedioxy) moiety, which were generally found to be inactive as exemplified by (+)-cassythicine (9).

[Study of plasma and hepatic hydrolysis of nitroxinil derivatives]. / Etude de l'hydrolyse plasmatique et hépatique de dérivés du Nitroxinil.

Seven esters derivatives of Nitroxinil were prepared and their structures were assigned by IR and 1H-NMR spectroscopy. The rate of plasma and hepatic hydrolysis were evaluated in vitro in sheep and rabbit. In view of this profile of activity, pivaloyl derivative merits evaluation, in vivo.

Synthesis and nematocidal activity of arylmercaptovinyltetrahydropyrimidines.

A set of mercaptovinyl tetrahydropyrimidines was synthesized in good yields by lithiation of 1,2-dimethyltetrahydropyrimidine with n-butyl lithium in tetrahydrofurane, followed by condensation with aromatic thioesters. Against three nematode genera, anthelminthic screening shows little activity; 2b and 2d were the most potent against Molinema dessetae.

[Diethyl benzylpiperazinomethyl and benzylpiperazinomethylbenzyl phosphonates as calcium inhibitors]. / Benzylpipérazinométhyl et benzylpipérazinométhylbenzyl phosphonates de diéthyle à visée inhibitrice calcique.

Two sets of phosphonic diethylester including a substituted benzylpiperazine moiety are synthesized. In spite of the spasmolytic or the calcium antagonistic potentialities of benzylpiperazine and phosphonic moieties, none of the six compounds, tested in vitro, exhibit any calcium antagonistic profile.

[The beta-adrenolytic activity of new arylmethyloxypropanolamine analogs of dioxadilol]. / Etude de l'activité beta adrénolytique de nouvelles arylméthyloxypropanolamines analogues du Dioxadilol.

A series of arylmethyloxypropanolamines structurally related to Dioxadilol has been synthesized and tested for their beta adrenolytic activity. Only one compound, the benzofuranic derivative 3c, exhibited a similar activity as Dioxadilol but was less potent than propranolol.

Influence of the vinyl group on the calcium antagonistic activity of analogues of Fostedil.

Four aryl vinyl diethyl benzylphosphonates related to Fostedil were synthesized and evaluated for their in vitro calcium-inhibitory activity. None of these compounds exhibited any calcium antagonistic profile. Unlike a series of diethyl-styryl benzylphosphonates, previously described, the presence of two aromatic rings linked by a vinyl group did not improve the calcium antagonistic activity.

[Synthesis and pharmacology of structural analogs of tienilic acids]. / Synthèse et approche pharmacologique d'analogues structuraux de l'acide tiénilique.

Three structural analogs of tienilic acid were synthetized and evaluated for their diuretic activity in the rat. Two compounds are alpha substituted tienilic acid derivatives by an alkylated group. The third one is a conformationally restricted derivative through a cyclization process. All compounds fall to increase the urinary flow in the pharmacological assay.

Inhibitory effect of new imidazole derivatives on the proliferation and nucleic acid synthesis of leukemic cells.

New derivatives of imidazothiazole and imidazobenzothiazole were tested in vitro for their potential antiproliferative activity. Four imidazobenzothiazole derivatives exhibited a cytotoxic activity against two leukemic cell lines, compound I being the most effective. Cell cycle kinetics studies showed that this drug delays the progression of cells from G1 to S and G2 M phases. An inhibitory effect on DNA and RNA synthesis was also observed. The antiproliferative effect of this compound, analogue of immunosuppressive agents, suggested that it could be of interest for a therapeutic use and for the synthesis of new derivatives.

Biodistribution and metabolism in rats and mice of bucromarone.

The metabolism and disposition of bucromarone, labeled with 14C on the chromone group, has been investigated in C3H mice and Wistar rats. In separate experiments, animals received 4.4 mmol/kg, iv or po, [14C]bucromarone hydrochloride or succinate. More than 90% of the administered radioactivity was excreted in bile, after iv and po administration. Less than 5 min after iv injection, radioactivity concentrated in all tissues, and blood concentration became very low as compared with its initial level. After po administration, no more than 10% of the dose was incorporated in the tissues. The discrepancy between the high biliary excretion and the low tissue and blood concentration after po administration suggested that bucromarone was well absorbed through the gastrointestinal tract; but after liver uptake, drug and its metabolites were excreted in the bile, less than 10% being distributed into the extrahepatic blood. Comparison of the iv and po areas under the plasma 14C-radioactivity concentration-time curves indicated a poor bioavailability of the molecule after po administration. Analysis of the radioactivity content of bile showed that bucromarone was extensively metabolized after both administration routes. Unchanged bucromarone and three main metabolites, monodesbutylbucromarone, didesbutyl bucromarone, and 2-(3-5-dimethyl-4-hydroxybenzoyl) chromone, amounting to 85% of the bile radioactivity, were identified by HPLC and mass spectrometry. These findings are consistent with a dealkylation of the N-dibutyl group, yielding potential pharmacologically active metabolites monodesbutyl and didesbutyl bucromarone.

Contribution of the diethyl phosphonate group to a first approach of calcium-inhibiting activity: study of a series of various substituted 2-phenylbenzothiazoles.

Eighteen substituted 2-phenyl benzothiazoles, nine of which are new, are described. Pharmacological investigation of these Fostedil analogues did not demonstrate the same calcium inhibitory properties shown by Fostedil. The enhancement induced by the diethyl phosphonate group is confirmed.

Synthesis and anthelminthic evaluation of 2-amidino-1,3,4-oxa and 1,3,4-thiadiazoles, structurally related to tetramisole.

N-(1,3,4-thiadiazol-2-yl) 1a-1k and N-(1,3,4-oxadiazol-2-yl-) amidines 2a-2g, N-(1,3-thiazol-2-yl) 3a, 3b and N-(1,3-benzothiazol-2-yl-)amidines 4a, 4b were synthesized and tested as anthelminthics, in vitro, against a free nematode (Rhabditis pseudoelongata), against infecting larvae of an intestinal parasite of rats (Nippostrongylus brasiliensis) and against infecting larvae of a filaria (Molinema dessetae).

Synthesis and pharmacological study of new N-methyl 1,2,3-triazole derivatives of 2-cyano chromones.

The reaction of various 2-cyano chromones with diazomethane generated a series of 21 N-methyl triazoles, with a benzopyrone moiety and divided into three isomeric groups. The anti-inflammatory, psychotropic and anti-allergic effects of these new compounds were evaluated. The results obtained did not confirm their expected potentialities.

[Synthesis of 2-aryl benzothiazoles and research on its antiparasitic activity]. / Synthèse d'aryl-2 benzothiazoles et recherche d'activité antiparasitaire.

Several 2-aryl benzothiazoles (with phenyl, naphthyl, thienyl and some oxygenated heterocycles) were synthesized. The anti-parasitic properties of these compounds were evaluated, in vitro and in vivo, against one Nematode Nippostrongylus brasiliensis and, in vitro against two Protozoaires Entamoeba histolytica and Trichomonas vaginalis. Only two compounds exhibited, in vitro a low nematicidal activity.

[Dihydro-5,6-imidazo[2,1-b]thiazoles, dihydro-2,3-imidazo[2,1-b]benzothiazoles, analogs of levamisole]. / Dihydro-5,6 imidazo[2,1-b]thiazoles, dihydro-2,3 imidazo[2,1-b]benzothiazoles, analogues du levamisole.

New compounds containing 5,6-dihydro imidazo[2,1-b]thiazole, 2,3,5,6-tetrahydro imidazo[2,1-b]thiazole and 2,3-dihydro imidazo[2,1-b]benzothiazole rings, substituted by heterocycles analogue to chromones, were synthesized and screened against three nematodes, in vitro. The results indicate moderate anthelmintic properties, compared to levamisole; nevertheless, some products exhibit a significant degree of activity.