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 aldose reductase inhibitory activities of novel thienocinnolinone derivatives.

A novel series of tetrahydrothieno[2,3-h]cinnolinone derivatives were synthesized and evaluated in vitro for their ability to inhibit aldose reductase (ALR2), an enzyme involved in the appearance of diabetic complications. Compounds 2e and 2j exert a remarkable inhibitory effect, with IC(50) of 7.6 and 18 microM, respectively. These compounds incorporate a valid pharmacophore for aldose reductase inhibitory activity represented by a thienocinnolinone template linked through a pentamethylene spacer to a carboxylic function.

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.

Synthesis and cytotoxicity of bis(benzo[g]indole-3-carboxamides) and related compounds.

A series of bis(benzo[g]indoles) bridged by CX-(CH2)nN(Me)(CH2)n-CX (X = O, S, H2; n = 2,3) was synthesized as bifunctional antitumor agents and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. The parent compounds 2a,b exhibited a good level of activity and derivates 2c-g,i,k demonstrated significant inhibitory effects, all with IC50 values in the low micromolar range. The thioamide analogue 2j showed less potency. It is interesting to note that introduction of substituents on the benzene ring of the benzo[g]indole portion of 2a,b did not affect activity, with the only exception of the 7,8-dichloro derivative 2h which became less potent. One member of this series, 2i, was then tested in the hollow fiber cell assay to evaluate, in a preliminary fashion, its in vivo antineoplastic activity. Molecular modelling studies were performed on amide 2a and thioamide 2j to explain the loss of activity of 2j as to 2a. Finally, compound 2a behaved as a typical DNA intercalating agent, as judged from viscosity measurements with Poly(dA-dT)...poly(dA-dT).

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).

Synthesis, molecular modeling, and opioid receptor affinity of 9, 10-diazatricyclo[4.2.1.1(2,5)]decanes and 2,7-diazatricyclo[4.4.0. 0(3,8)]decanes structurally related to 3,8-diazabicyclo[3.2. 1]octanes.

Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2. 1]octanes (DBO, 1) plays an essential role in modulating affinity toward mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8) arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2. 1.1(2,5)]decane (4) and 2,7-diazatricyclo[4.4.0.0(3,8)]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest mu-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

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.

Synthesis and dopamine D2-like receptor binding affinity of substituted 5-phenyl-pyrrole-3-carboxamides.

A series of 5-p-substituted phenyl-pyrrole-3-carboxamide derivatives was designed as hybrid analogs of the dopamine D2-like 5-phenyl-pyrrole and heterocyclic carboxamide antipsychotics. The title compounds were synthesized and evaluated for dopamine D2-like receptor by means of [3H]YM-09151-2 receptor binding assay. The compound bearing a 1-ethyl-2-methyl-pyrrolidine moiety as the basic part of 5-phenyl-pyrrole-3-carboxamide derivative 1a together with its 2-chloro analog 1f were found to possess affinity in the low micromolar range. Substituted phenyl-pyrrolecarboxamides containing groups such as F, Cl, NO2, CH3, at the 4-position of the phenyl ring, gave ligands with lower D2-like affinity.

Synthesis and in vitro anticancer activity evaluation of biscarbamic esters of 2,3-bis(hydroxymethyl)-1-methyl-7- and 7,8-substituted-benzo[g]indoles.

A series of various bis(hydroxymethyl) carbamate derivatives of 7-mono- and 7,8-disubstituted-1-methyl-benzo[g]indoles was prepared in order to evaluate their cytostatic and cytotoxic activities in vitro. Compounds 2a-h showed significant tumor growth inhibition activity and were more potent than the 4,5-dihydrobenzo[g]indole analogues previously described. Compound 2a was the most active in this series, showing high activity and selectivity for some human cancer cell lines in the National Cancer Institute screen.

Benzocondensed derivatives as rigid analogues of the mu-opioid agonist 3(8)-cinnamyl-8(3)-propionyl-3,8-diazabicyclo[3.2.1]octanes: synthesis, modeling, and affinity.

A new series of rigid analogues (1a-g, 2a-g) of the previously reported analgesic 3-cinnamyl-8-propionyl-3,8-diazabicyclo[3.2.1]octane (I) and its reverted isomer 3-propionyl-8-cinnamyl (II) were synthesized, in which the cinnamyl substituent is incorporated in benzocondensed bicyclic systems. Binding assays for the affinity towards mu receptors indicated that, while in the reverted series 2 the beta-naphthylmethyl (2d) and the benzocycloheptenylmethyl derivative (2g) favorably compared with II, all compounds 1 displayed a mu-affinity lower than that of the parent I. Modeling studies suggest that the flexibility of the cinnamyl side chain plays an important role for activity.

Synthesis and D2-like binding affinity of 4,5-dihydro-1H-benzo[g]indole-3-carboxamide derivatives as conformationally restricted 5-phenyl-pyrrole-3-carboxamide analogs.

A series of 4,5-dihydro-1H-benzo[g]-indole-3-carboxamide derivatives 2a-g were synthesized as conformationally restricted analogs of the dopamine D2-like 5-phenylpyrrole-3-carboxamide ligands and evaluated for their affinity for the dopamine D2-like receptors. In this series, N3-[(1-ethyltetrahydro-1H-2-pyrrolyl)methyl]-4,5-dihydro-1H-benzo[ g]indole- 3-carboxamide (2a) showed the highest affinity for D2-like receptors (IC50 = 160 nM). Replacement of the N-(1-ethyl-2-pyrrolidinyl)methyl side chain with a 2-(N,N-diethylamino)ethyl or a 1-benzyl-4-piperidinyl group (2b, 2d) decreased affinity for the D2-like receptor. The other compounds tested were found to be devoid of D2-like binding affinity.

Synthesis and mu-opioid receptor affinity of a new series of nitro substituted 3,8-diazabicyclo[3.2.1]octane derivatives.

A new series of analogues (1c-j; 2c-i) of the previously reported analgesic 3,8-diazabicyclo[3.2.1]octanes (1a,b; 2a,b) was synthesized and tested for their affinity towards mu-opioid receptors. Modifications were introduced either at the cinnamyl or the acyl side chains. The majority of the new compounds, with the exception of 1c,j and 2c, showed Ki values better or comparable with those of the models.

Synthesis and pharmacological evaluation of 4,4a,5,6-tetrahydro-7,8-disubstituted-benzo[h]cinnolin-3(2H)-ones.

7,8-disubstituted-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-ones 2-4 have been synthesized and tested in comparison with the 8-acetylamino-4,4a,5, 6-tetrahydrobenzo[h]cinnolin-3(2H)-one 1 reported to be a potent antihypertensive and antithrombotic agent. Binding studies on phosphodiesterase (PDE) isoenzymes showed that the test compounds exhibited a modest affinity towards PDE III which in the case of 2, 3 was higher than that of 1. In vivo tests indicated that compounds 2 and 4 displayed lower hypotensive activity than model 1 while 3 was inactive. Conversely, compounds 2-4 were as potent as 1 in inhibiting collagen-induced platelet aggregation.