The novel cannabinoid antagonist SM-11 reduces hedonic aspect of food intake through a dopamine-dependent mechanism.

Cannabinoids, endogenous and exogenously administered, are known to positively regulate food intake and energy balance. Since CB1 receptor antagonists reduce food intake and antagonize overweight, we developed a new CB1 receptor antagonist in an attempt to identify a compound with potential application in overeating disorders. The newly developed SM-11 compound dose-dependently decreases food intake in rats by 15-20%. Moreover, SM-11 reduces self-administration of palatable food in both food restricted and ad libitum fed rats, suggesting an action on the hedonic component of food intake. Thus, we next tested the effect of SM-11 on the stimulating properties of the CB1 receptor agonist WIN55,212-2 (WIN) on the electrophysiological activity of Nucleus Accumbens-projecting dopaminergic neurons of the ventral tegmental area (VTA). SM-11 fully and readily antagonized the WIN-induced increments in single spiking and burst firing of antidromically-identified dopamine neurons. When administered to naïve (no WIN-pretreated) rats, SM-11 did not alter basal neuronal activity, thereby suggesting a pure antagonistic profile. SM-11 thus appears as a promising candidate in the search of potential anti-obesity medications.

Synthesis of biologically active bridged diazabicycloheptanes.

The chemistry underlying how diazabicycloheptanes are assembled is described, subdivided according to chemical structure of two types, the 3,6 diazabicyclo[3.1.1]heptane and the 2,5-diazabicyclo[2.2.1]heptane ring system. Detailed information on myriad of activities of compounds derived from the two scaffolds are reported.

An overview on different classes of viral entry and respiratory syncitial virus (RSV) fusion inhibitors.

The therapeutic approach to AIDS is based on the combination of different drugs in the highly active antiretroviral therapy (HAART) regimen. These drugs have a wide variety of side effects, and some strains of HIV can develop resistance: for these reasons new anti-HIV drugs are needed. In the wide field of anti-HIV medicine this review covers different classes of drugs which inhibit viral entry: in particular the classification of main categories, their mode of action and some new candidates for AIDS therapy are contemplated. Also covered in this review are respiratory syncytial virus (RSV) fusion inhibitors.

Thienocinnolinone alkanoic acid derivatives as aldose reductase inhibitors.

A new series of 8-halogen-4,4a,5,6-tetrahydrothieno[2,3-h]cinnolinone-N2-alkanoic acids was prepared and tested for aldose reductase (ALR2) inhibitory activities. These compounds showed significant inhibitory activity against bovine lens ALR2, with the best compound 2e showing an IC(50) value of 31.4 microM. The presence of the C8-substituents here studied (Cl, Br) on the thienocinnolinone scaffold caused a decrease of the inhibitory potency by a factor of about 4 with respect to the unsubstituted parent compound, while the presence of a C8-methyl group, considered in a previous paper decreased the activity by a factor of about 2. Moreover, the length of the N2 alkanoic chain influences strongly the enzyme inhibitory activity. While most of the carboxylic acids ALR2 inhibitors are acetic acid derivatives, in the case of thienocinnolinone compounds, homologues higher than acetic acids showed to be more active.

Synthesis and cytotoxicity of substituted 2-benzylnaphth[2,3-d]imidazoles.

Designed as a new series of so called "bivalent ligand" containing the proposed 2-benzylnaphthimidazole-type structure, a number of 2-benzylnaphth[2,3-d]imidazoles, bearing various substituents, have been prepared by a synthetic approach involving an heterocyclization of 2,3-diaminonaphthalene 4 with appropriate imidates 3 (for 1b-i) followed by alkylation (for 1j-l) with the desired alkylating agent. Compounds 1b-f, h-l were subjected to primary biological evaluation for cancer cell growth inhibition (one-dose, three-cell assay), and the four most active terms, 1c, h, i and j, were then evaluated for their cytotoxic profiles in the National Cancer Institute's (NCI) human disease-oriented, 60 cell line, in vitro antitumor screening protocol. Among them, two compounds (1h and 1i) are the most representatives demonstrating not only high growth-inhibitory activities against some leukemia cancer cells, but also fairly good activities against the growth of certain cell lines of some solid tumors.

Synthesis and cytotoxicity evaluation of thiophene analogues of 1-methyl-2, 3-bis(hydroxymethyl)benzo[g]indole bis[N-(2-propyl)carbamate].

The cytotoxicity of the bis[N-(2-propyl)carbamates] 2 and 3 which are linked to thieno[i,j-g]indole scaffolds through methylene bridges were studied as thiophene analogues of prototype 1. Compounds 2 and 3 were evaluated in vitro against 60 human-tumor cell lines derived from nine cancer-cell types and demonstrated, for compound 3 not only strong growth-inhibitory activities against leukemia cancer cells, but also fairly good activities against the growth of certain renal and ovarian cancer cell lines. Compound 2, the thieno[2,3-g]indole bis-carbamate, possessed only significant (MG-MID log10 GI50 = -4.89) and selective cytoxicity against NCI-HOP92 (non-small cell lung), MALME 3M (melanoma) and IGROV 1 (ovarian) cancer cell with log10 GI50 values of -5.66, -5.48 and -5.47, respectively.

Synthesis and anti-HIV-1 activity of new delavirdine analogues carrying arylpyrrole moieties.

In our search for novel anti-human immunodeficiency virus (HIV)-1 agents, 14 delavirdine analogues were synthesized and evaluated as potential anti-HIV-1 agents in cell-based assays. Compound 1Aa exhibited potent and selective anti-HIV-1 activity in acutely infected MT4 cells, with effective concentration (EC50) values in the submicromolar range.

Synthesis and analgesic-antiinflammatory activities of novel acylarylhydrazones with a 5-phenyl-4-R-3-pyrrolyl-acyl moiety.

A new series of arylidene 5-phenyl-4-R-pyrrole-3-carbohydrazides 1a-j were prepared and evaluated for their analgesic-antiinflammatory activities. All synthesized compounds showed a significant analgesic action in mice after intraperitoneal administration at a dose of 100 microM/kg. Two of these, 1b, (4'-methylbenzylidene)-5-phenyl-1H-pyrrole-3-carbohydrazide, and 1d, (4'-chlorobenzylidene)-5-phenyl-1H-pyrrole-3-carbohydrazide, were found to be more potent as antinociceptive agents respect to dipyrone and indometacin, used as reference drugs. Among compounds 1, only 1b showed a moderate antiinflammatory effect in rats while 1d proved to be a potent non antiinflammatory analgesic.

Pyridazine N-oxides. III. Synthesis and "in vitro" antimicrobial properties of N-oxide derivatives based on tricyclic indeno[2,1-c]pyridazine and benzo[f]cinnoline systems.

A number of 9H-indeno[2,1-c]pyridazine N-oxides (3a-c) and benzo[f]cinnoline N-oxides (4,5a-c) have been synthesized and tested for antimicrobial activity. All new products were inactive against Gram negative bacteria and fungi. In contrast, among the compounds synthesized, 3b, 4b and 5b showed a moderate activity against Gram positive Staphylococcus aureus and Staphylococcus epidermidis. Of the present series, the 9-nitro-benzo[f]cinnoline N-oxide 5b possessed the highest activity especially against Trichomonas vaginalis (MIC = 3.9 micrograms/ml).

Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors.

A new series of thieno[3,2-h]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6-hexahydrothieno [3,2-h]cinnolin-3-one 1, a weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C4a-methyl, C7-acetylamino, C7 and C8-nitro substitution, and C4-C4a olefination provided no increase in activity relative to 1, C8-acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,2-h]cinnolinone inhibitors might bind to MMP-8, the unsubstituted compound 9 was docked into the MMP-8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically-active zinc ion but preferably interact with the peptide-binding region of the active site.

Synthesis, modelling, and mu-opioid receptor affinity of N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicycl.

A series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1a-g) and of reverted N-3-propionyl-N-9-arylpropenyl isomers (2a-g), as homologues of the previously reported analgesic 3,8-diazabicyclo[3.2.1]octanes (I-II), were synthesized and evaluated for the binding affinity towards opioid receptor subtypes mu, delta and kappa. Compounds 1a-g and 2a-g exhibited a strong selective mu-affinity with Ki values in the nanomolar range, which favourably compared with those of I and II. In addition, contrary to the trend observed for DBO-I, II, the mu-affinity of series 2 is markedly higher than that of the isomeric series 1. This aspect was discussed on the basis of the conformational studies performed on DBN which allowed hypotheses on the mode of interaction of these compounds with the mu receptor.