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.

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.

Anti-inflammatory and analgesic amides: new developments.

A series of substituted N-cycloalkyl benzamides, cinnamamides, and indole-3-carboxamides were synthesized and evaluated for their analgesic, antiinflammatory activities as well as for their gastrointestinal irritation liability. Indomethacin was used as reference drug in both tests. Compounds 1k, 1b, 1h, 1j, and 1g were the most active in the antiinflammatory paw edema inhibition test, with a sharply dose-dependent effect. In terms of the analgesic activity (acetic acid writhing test), the most active compound was 5a followed by 3a, but many other compounds were found to have a non-negligible potency. Even in this case, the effect was dose dependent.

Synthesis of substituted N-(4-piperidyl)-N-(3-pyridyl)amides with antiarrhythmic activity. Note 1.

The synthesis of analogues of N,2-diphenyl-N-(4-piperidyl)acetamide endowed with antiarrhythmic activity is reported. Benzoyl, cinnamoyl, acetyl and propionyl groups replace the phenacyl group as N-acyl substituent, while pyridine replaces benzene as aromatic ring bound to the amide nitrogen. The title compounds were evaluated for antiarrhythmic activity on experimental arrhythmias induced by aconitine in rats. The presence of a n-propyl chain and an unsubstituted cinnamoyl moiety (1j) gives the highest protection against aconitine induced extrasystoles while the best efficacy against lethal effects is due to the presence of a n-propyl chain and an acetyl moiety (1m).

Synthesis of N-[4-(propyl)cyclohexyl]-amides with anti-inflammatory and analgesic activities.

Seventeen (un)substituted N-[4-(propyl)cyclohexyl]-amides (6a-h, 7a-h and 8) were synthesized and tested as anti-inflammatory and analgesic agents. The substituents on the aromatic ring were chosen in order to study the influence of electron-withdrawing or electron-donating residues, that change the electronic density on the aromatic moiety. The pharmacological results allow drawing some preliminary considerations on structure-activity relationships.

Synthesis of N-[4-(alkyl)cyclohexyl]-substituted benzamides with anti-inflammatory and analgesic activities.

Two series of N-[4-(alkyl)cyclohexyl]-substituted benzamides, i.e. a series of N-[4-(tert-butyl)cyclohexyl]-substituted benzamides and a series of N-[4-(ethyl)cyclohexyl]-substituted benzamides, were synthesised and evaluated for their anti-inflammatory and analgesic potencies, and gastrointestinal irritation liability.

Fungicidal activity of some o-nitrophenyl-hydrazones.

The antimycotic activity of 16 o-nitrophenylhydrazones against strains of Hansenula anomala, Saccharomyces cerevisiae, Candida parapsylosis, and Cryptococcus albidus was tested. All 16 compounds inhibited growth of the yeast strains. The inhibitory activity of the 4 methyl-derivatives substituted on the aromatic nucleus was particularly significant.

Isolation, characterization and pharmacological activity of Magydaris pastinacea (Lam) Paol. glucosides.

The glycoside fraction of fresh rhizomes from Magydaris pastinacea (Lam.) Paol. was separated from the alcoholic extract using the method of Kobayashi et al. The fraction was found to have six main constituents, the most abundant of which had previously been isolated and identified as 7-O-beta-D-glucopyranosyl-8-(2',3'-dihydroxy-3-methyl-butylcoumarin++ +). The present paper describes the separation and characterization of the other constituents, all with coumarin or furancoumarin structures. Pharmacological experiments to test these compounds as platelet antiaggregants are also reported.