Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding.

RATIONALE: Atypical dopamine (DA) transport blockers such as modafinil and its analogs may be useful for treating motivational symptoms of depression and other disorders. Previous research has shown that the DA depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards a low-effort bias in effort-based choice tasks. This is consistent with human studies showing that people with major depression show a bias towards low-effort activities. OBJECTIVES: Recent studies demonstrated that the atypical DA transport (DAT) inhibitor (S)-CE-123 reversed tetrabenazine-induced motivational deficits, increased progressive ratio (PROG) lever pressing, and increased extracellular DA in the nucleus accumbens. In the present studies, a recently synthesized modafinil analog, (S, S)-CE-158, was assessed in a series of neurochemical and behavioral studies in rats. RESULTS: (S, S)-CE-158 demonstrated the ability to reverse the effort-related effects of tetrabenazine and increase selection of high-effort PROG lever pressing in rats tested on PROG/chow feeding choice task. (S, S)-CE-158 showed a high selectivity for inhibiting DAT compared with other monoamine transporters, and systemic administration of (S, S)-CE-158 increased extracellular DA in the nucleus accumbens during the behaviorally active time course, which is consistent with the effects of (S)-CE-123 and other DAT inhibitors that enhance high-effort responding. CONCLUSIONS: These studies provide an initial neurochemical characterization of a novel atypical DAT inhibitor, and demonstrate that this compound is active in models of effort-related choice. This research could contribute to the development of novel compounds for the treatment of motivational dysfunctions in humans.

Water/Alkali-Catalyzed Reactions of Azides with 2-Cyanothioacetamides. Eco-Friendly Synthesis of Monocyclic and Bicyclic 1,2,3-Thiadiazole-4-carbimidamides and 5-Amino-1,2,3-triazole-4-carbothioamides.

The reactions of thioamides with azides in water were studied. It was reliably shown that the reaction of 2-cyanothioacetamides 1 with various types of azides 2 in water in the presence of alkali presents an efficient, general, one-step, atom-economic, and eco-friendly method for the synthesis of 1,2,3-thiadiazol-4-carbimidamides 5 and 1,2,3-triazole-4-carbothioamides 4. This method can be extended to the one-pot reaction of sulfonyl chlorides and 6-chloropyrimidines 2'o with sodium azide, leading to final products in higher yields, that is, avoiding the isolation of unsafe sulfonyl azides. The method was furthermore applied to the reaction of N,N'-bis-(2-cyanothiocarbonyl)pyrazine 1h with sulfonyl azides to afford bicyclic 1,2,3-thiadiazoles 8 and 1,2,3-triazoles 9 connected via a 1,1'-piperazinyl linker. 2-Cyanothioacetamides 1 were also shown to react with aromatic azides in water in the presence of alkali to afford 1-aryl-5-amino-1,2,3-triazole-4-carbothioamides 11. In contrast to aromatic azides and similarly to sulfonyl azides, 6-azidopyrimidine-2,4-diones 2o-q react with cyanothioacetamides to form N-pyrimidin-6-yl-5-dialkylamino-1,2,3-thiadiazole-4-N-l-carbimidamides 12. A mechanism was proposed to rationalize the role of water in changing the reactivity of azides toward 2-cyanothioacetamides.

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of ß-isoxazolyl- and ß-imidazolyl enamines with nitrile oxides.

Reactions of ß-azolyl enamines and nitrile oxides were studied by both experimental and theoretical methods. (E)-ß-(4-Nitroimidazol-5-yl), (5-nitroimidazol-4-yl) and isoxazol-5-yl enamines smoothly react regioselectively at room temperature in dioxane solution with aryl, pyridyl, and cyclohexylhydroxamoyl chlorides without a catalyst or a base to form 4-azolylisoxazoles as the only products in good yields. The intermediate 4,5-dihydroisoxazolines were isolated as trans isomers during the reaction of (E)-ß-imidazol-4-yl enamines with aryl and cyclohexylhydroxamoyl chlorides. Stepwise and concerted pathways for the reaction of ß-azolyl enamines with hydroxamoyl chlorides were considered and studied at the B3LYP/Def2-TZVP level of theory combined with D3BJ dispersion correction. The reactions of benzonitrile oxide with both E- and Z-imidazolyl enamines have been shown to proceed stereoselectively to form trans- and cis-isoxazolines, respectively. The preference of E-isomers over Z-isomers, driven by the higher stability of the former, apparently controls the stereoselectivity of the investigated cycloaddition reaction with benzonitrilе oxide. Based on the reactivity of azolyl enamines towards hydroxamoyl chlorides, a novel, effective catalyst-free method was elaborated to prepare 4-azolyl-5-substituted isoxazoles that are otherwise difficult to obtain.