Ring-fused thiadiazines as core structures for the development of potent AMPA receptor potentiators.

Amongst ionotropic glutamatergic receptors, the AMPA receptor subtype has been recognized as a major contributor to the fast excitatory neurotransmission in the central nervous system and the expression and maintenance of longterm potentiation. This receptor subtype also represents an interesting target to develop innovative therapeutic drugs such as positive allosteric modulators (AMPA receptor potentiators) since the enhancement of AMPA signals is expected to be beneficial in the management of several neurological disorders such as depression, schizophrenia, Parkinson's disease and learning-memory deficits linked to Alzheimer's disease. This article is dedicated to the use of (hetero) aromatic ring-fused thiadiazines (i.e. benzo- pyrido- and thienothiadiazines) as core structures for the discovery of new positive allosteric modulators of AMPA receptors. Recent advances exploring other chemotypes in the field of AMPA potentiators is the object of a separate review of the present issue.

A potent and selective NPY Y5 antagonist reduces food intake but not through blockade of the NPY Y5 receptor.

AIM: These studies were performed to test the hypothesis that endogenous neuropeptide Y (NPY) acting on the NPY Y(5) receptor subtype contributes to the control of food intake. The hypothesis was tested using S 25585-a newly synthesized NPY Y(5) receptor antagonist. METHODS AND RESULTS: S 25585 was shown to be a high-affinity antagonist of the NPY Y(5) receptor subtype (IC(50) 5 nM) with no significant affinity toward other NPY receptor subtypes and over 40 other receptors, channels or uptake systems. S 25585 (7.5 mg/kg, i.p.) did not induce a conditioned taste aversion, significantly alter need-induced sodium appetite or induce pica, suggesting that at this dose the compound did not induce illness or malaise. In satiated rats, S 25585 (5.0 and 7.5 mg/kg, i.p.) significantly decreased the overfeeding induced by i.c.v. injection of NPY (1 microg) and the highly selective NPY Y(5) receptor agonist [hPP(1-17), Ala(31), Aib(32)]NPY (0.7 microg). In rats fasted for 4 h immediately before the dark phase, analysis of the microstructure of feeding behavior revealed that S 25585 significantly increased latency to eat and significantly decreased the duration and size of the meals without altering the meal number or eating rate. Analysis of the behavioral satiety sequence at this time revealed that the animals passed through the normal pattern of feeding, grooming and resting. Although S 25585 appeared to be influencing a physiological system controlling appetite, this does not involve the NPY Y(5) receptor since the antagonist also markedly reduced food intake in the NPY Y(5) knockout mouse. CONCLUSIONS: The results presented do not support a role for the NPY Y(5) receptor in the control of food intake. The results further illustrate that it is imperative that the activity of any new NPY Y(5) antagonist be assessed in the NPY Y(5) knockout mouse before assuming that its effect on food intake is due to blockade of this receptor.

Synthesis and cytotoxicity of artemisinin derivatives containing cyanoarylmethyl group.

A series of 12alpha-deoxoartemisinyl cyanoarylmethyl dicarboxylates (4a-4o), dicarboxylic acids 12alpha-deoxoartemisinyl ester cyanoarylmethyl amide (5a-5k), and dicarboxylic acids 12alpha-deoxoartemisinyl ester N-methylcyanoarylmethyl amide (6a-6l), showing moderate cytotoxicity against P388 and L1210 cells were prepared. They induced the significant accumulation of L1210 and P388 cells in the G1 phase of the cell cycle. This mechanism of action was quite different from that of the majority of cytotoxic compounds used in the chemotherapy of cancer. Compound 4b possessed better cytotoxicity than the other compounds.

Antitumor agents. Synthesis and biological evaluation of new compounds related to podophyllotoxin, containing the 2,3-dihydro-1,4-benzodioxin system.

New compounds with naphtho-fused systems were synthesized and evaluated as antitumor agents. The naphtho-fused systems 6 and 7, synthesized from the hydroxy-acetal, exhibit antitumor activity. The bis(phenylthio) derivatives were considered as possible precursors for lignan lactones (11). The hydroxy-naphthalen 6 showed a significant antineoplastic activity.

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).

Novel antitumor artemisinin derivatives targeting G1 phase of the cell cycle.

Modification of artemisinin structure led us to the discovery of a novel class of antitumor compounds. These artemisinin derivatives containing cyano and aryl groups showed potent antiproliferative effect in vitro against P388 and A549 cells. This activity was reflected in P388 murine leukemia by an accumulation of cells in G1 phase, and induction of apoptosis.

Synthesis and pharmacological evaluation of analgesic 6-substituted 2(3H)-benzothiazolones.

A series of novel 6-substituted-2(3H)-benzothiazolones were synthesized and studied as analgesic agents. Among these compounds, two of them were found to exhibit potent analgesic activity in several in vivo tests (acetic acid writhing, Koster, carrageenan and PGE2 hyperalgesia). In these tests the most active compound of this series, i.e. 6-benzoyl-2(3H)-benzothiazolone (4a) was found to be superior to acetylsalicylic acid and equivalent to glafenine. The present study allows to conclude that 4a represents a new type of antinociceptive agent acting in periphery by inhibiting the cyclo-oxygenase pathway and promoting the release of an opioid peptide.

Synthesis and binding studies on a new series of arylpiperazino benzazol-2-one and benzoxazin-3-one derivatives as selective D4 ligands.

A series of new arylpiperazinomethyl derivatives was designed and studied as potential D4 ligands. The synthesis of these compounds required an original synthetic route. Some of the tested compounds were found to be as potent as clozapine at D4 receptors. Moreover, compounds which displayed a high D2/D4 selectivity ratio (>122) were selected for further pharmacological evaluation.

[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.

Synthesis and cytotoxic activity of 2-dialkylaminoethylamino substituted xanthenone and thioxanthenone derivatives.

The synthesis and biological evaluation of some new pyranoxanthenones and pyranothioxanthenones, substituted with flexible amino side-chains, and their evaluation as potential antitumor agents is described. The cytotoxic activity of the compounds and their eventual selective effect on a phase of the cell cycle were evaluated in vitro, using the murine lymphocytic L1210 leukemia cell line. The new aminoderivatives exhibited highly potent cytotoxicity against the leukemia L1210 cell line when compared to acronycine. All the compounds induced a partial accumulation of cells in the G2 + M phase of the cell cycle.

Semisynthesis and cytotoxicity of styryl-lactone derivatives.

The cytotoxicity and the cell-cycle action of altholactone (1), goniofufurone (2), and eight altholactone derivatives (5-12), were determined in vitro on L-1210 cells. Semisyntheses and structure-activity relationships of these compounds are described. The results of this study suggest that the cytotoxicity of altholactone (1), 11-nitro-altholactone (8), and 7-chloro-6,7-dihydroaltholactone (10) is due to the accumulation of the cells in the G2 + M phase of the cell cycle.

Isomers of substituted 3-benzo[b]furyl and 3-thienylaminobutyric acids as potent ligands of the GABA-B receptor: synthesis and preparative liquid chromatographic separation.

Baclofen (4-amino-3-(4-chlorophenyl)butyric acid) is the only selective agonist for GABA-B receptors. Its R-(-)-enantiomer is about 100 times more active than the S-(+)-enantiomer. In the search for new compounds that bind to GABA-B receptors, it is very important to clarify the structural requirements. The authors report the synthesis and separation of isomers of various 3-heteroaromatic (benzo[b]furan and thiophen) aminobutyric acids. The 4-amino-3-(7-methylbenzo[b]furan-2-yl)butanoic acid is a potent and specific ligand for GABA-B receptors, with an IC50 value of 5.4 microM for the displacement of [3H] GABA.

Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands.

A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogues of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n propyl urea derivative (27) is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This molecule, compound 12, or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclinical development.

Novel benzothiazolin-2-one and benzoxazin-3-one arylpiperazine derivatives with mixed 5HT1A/D2 affinity as potential atypical antipsychotics.

Since it was known that 5HT properties (5HT1A agonism or 5HT2A antagonism) combined with D2 antagonism may lead to atypical antipsychotic drugs, a series of 19 benzothiazolin-2-one and benzoxazin-3-one derivatives possessing the arylpiperazine moiety was prepared, and their binding profiles were investigated. All tested compounds displayed very high affinities for the 5HT1A and D2 receptors. Therefore, further pharmacological studies were carried out on selected compounds (24, 27, 30, 46, and 47). This evaluation in rats clearly revealed potent antipsychotic properties along with a decrease of extrapyramidal side effects. These derivatives are currently under preclinical development.

Substituted pyrido[3,2-b]oxazin-3(4H)-ones: synthesis and evaluation of antinociceptive activity.

A new series of N-substituted pyrido[3,2-b]oxazinones has been synthesized, pharmacologically evaluated, and compared with acetyl salicylic acid. The compound with the maximal combination of safety and analgesic efficacy was 4-¿3-[4-(4-fluorophenyl-1-piperazinyl)propyl]¿-2H-pyrido[3,2-b]-1, 4-oxazin-3(4H)-one (6c) with ED50 values of 12.5 mg/kg po (mouse: phenylquinone writhing test) and 27.8 mg/kg po (rat: acetic acid writhing test), respectively. Compound 6c proved to be more active than aspirin with a safety index of 5.1.

6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones: synthesis and evaluation of antinoceptive activity.

Series of 6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones incorporating structural modifications both in the alkyl chain and basic amino moiety were tested for their analgesic efficacy and safety in mice and rats. Two of the synthesised compounds, 4a (3-methyl-6-[(4-phenyl-1-piperazinyl)methyl]oxazolo[4,5-b]pyridin-2(3H)-one) and 12a (3-methyl-6¿1-[2-(4-phenyl-1-piperazinyl)ethan-1-ol]¿oxazolo[4,5-b]pyridin- 2(3H)-one) were found to be more potent than aspirin with ED50 values of 26 (16.1-42.4) and 15.5 (11.4-21.2) mg/kg po (mouse, phenylquinone writhing test) respectively and 6 (3.1-9.8) and 5.5 (3.5-8.8) mg/kg po (rat, acetic acid writhing test). Compounds 4a and 12a proved to be potent nonopioid nonantiinflammatory analgesics but unfortunately have sedative properties at relatively low doses (respectively 64 and 16 mg/kg po, mice).

Novel and selective partial agonists of 5-HT3 receptors. 2. Synthesis and biological evaluation of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines.

In continuation of our previous work on piperazinopyrrolothienopyrazine derivatives, three series of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifications performed within these new series led to structure-activity relationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 receptors with a selectivity higher than 10(6). Four of the high-affinity 5-HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrrolopyrazine and the pyrroloquinoxaline series and were characterized in vitro and in vivo as agonists or partial agonists. Compound 8a was also evaluated in the light/dark test where it showed potential anxiolytic-like activity at very low doses per os.

Novel indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives. Structure-activity relationships for high inhibition of human LDL peroxidation.

Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and evaluated in order to determine the necessary structural requirements for a high inhibition of human LDL copper-induced peroxidation. Various modulations were systematically performed on the indole and cycloalkeno[1,2-b]indole nuclei as well as on the carboxamide moiety. The best compounds (3c, 3e, 7c, 7f, 7h, 7g, and 7o) are between 5 and 30 times more active than probucol itself. Two of these compounds (3c and 7o) were selected for complementary in vitro and in vivo investigations, which have shown additional properties of interest for the treatment and the prevention of atherosclerosis injuries. Compound 3c was found to have some antiinflammatory properties while compound 7o was proved to protect endothelial cells from the direct cytotoxicity of oxidized LDL with some additional calcium channel blocking properties.

3-amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans].

In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.

Effects of S20787 on pHi-regulating mechanisms in isolated rat ventricular myocytes.

Intracellular pH (pHi) regulation in the heart relies on the activity of three membrane mechanisms: the Na+/H+ exchange and an Na+, HCO3(-)-dependent transport, both activated after an acid load, and the Cl-/HCO(3-) exchange, activated by an intracellular alkalinization. Whereas several specific inhibitors of Na+/H+ exchange exist, distinguishing between the two HCO3(-)-dependent mechanisms remains difficult, especially near the steady state, because of the lack of specific inhibitors. To detect one such inhibitor, we tested the effects of S20787 on pHi regulation in the rat isolated ventricular myocytes. Intracellular pH was recorded with the fluorescent probe carboxy-SNARF-1. The NH4Cl (10 mM) prepulse method was used to induce an acid load to activate the dual acid extrusion system; Cl-/HCO3- exchange was activated with the acetate (40 mM) prepulse method. Our results showed that (a) a high dose (5.10(-6) M) of S20787 did not change intracellular intrinsic buffering power, beta i; (b) the dual acid extrusion system was unaffected by S20787 in the concentration range of 10(-11)-10(-6) M; and (c) S20787 partially inhibited (approximately 50%) the activity of Cl-/HCO3- exchange in a dose-dependent manner, with an IC50 of 8.8 x 10(-10) M. This inhibitory action of S20787 did not change the steady-state pHi after 5-10 min application. Our results demonstrate that S20787 is a specific and potent partial inhibitor of Cl-/HCO3- exchange in cardiac cells.