Antiseizure Activity of Novel γ-Aminobutyric Acid (A) Receptor Subtype-Selective Benzodiazepine Analogues in Mice and Rat Models

The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for α2β3γ2 and α3β3γ2 GABAA-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, ip) were observed for compounds 2-4 in the subcutaneous metrazole seizure (scMET) test. In rats orally (po) the TI was >5 to 105. These compounds represent novel leads in the search for anticonvulsants devoid of sedative, ataxic and amnestic side effects

Barberou

Dictionnaire Gustave Flaubert, sous la direction d’Éric Le Calvez [avec la collaboration d’A. Carrico, M. F. Davì Trimarchi, S. Dord-Crouslé, A. Herschberg Pierrot, C. Ippolito, É. Le Calvez, B. Magaudda, S. Mangiapane, K. Matsuzawa, R. M. Palermo Di Stefano, F. Pellegrini, N. Petibon, T. Poyet, J. Thomas et F. Vatan] ; Classiques Garnier, 2017 ; coll. Dictionnaires et synthèses ; 1259 page

Stereospecific Approach to the Synthesis of Ring‑A Oxygenated <i>Sarpagine</i> Indole Alkaloids. Total Synthesis of the Dimeric Indole Alkaloid <i>P</i>‑(+)-Dispegatrine and Six Other Monomeric Indole Alkaloids

The first regio- and stereocontrolled total synthesis of the bisphenolic, bisquaternary alkaloid (+)-dispegatrine (<b>1</b>) has been accomplished in an overall yield of 8.3% (12 reaction vessels) from 5-methoxy-d-tryptophan ethyl ester (<b>17</b>). A crucial late-stage thallium­(III) mediated intermolecular oxidative dehydrodimerization was employed in the formation of the C9–C9′ biaryl axis in <b>1</b>. The complete stereocontrol observed in this key biaryl coupling step is due to the asymmetric induction by the natural <i>sarpagine</i> configuration of the monomer lochnerine (<b>6</b>) and was confirmed by both the Suzuki and the oxidative dehydrodimerization model studies on the tetrahydro β-carboline (<b>35</b>). The axial chirality of the lochnerine dimer (<b>40</b>) and in turn dispegatrine (<b>1</b>) was established by X-ray crystallography and was determined to be <i>P</i>(S). Additionally, the first total synthesis of the monomeric indole alkaloids (+)-spegatrine (<b>2</b>), (+)-10-methoxyvellosimine (<b>5</b>), (+)-lochnerine (<b>6</b>), lochvinerine (<b>7</b>), (+)-sarpagine (<b>8</b>), and (+)-lochneram (<b>11</b>) were also achieved via the common pentacyclic intermediate <b>16</b>

Brønsted Acid Mediated Cyclization of Enaminones. Rapid and Efficient Access to the Tetracyclic Framework of the <i>Strychnos</i> Alkaloids

The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core <b>17</b> of the <i>Strychnos</i>-<i>Aspidosperma</i> alkaloids is described. Enaminone <b>16</b>, synthesized in high yield, has been cyclized under the influence of a Brønsted acid to provide the core tetracyclic framework <b>17</b> of the <i>Strychnos</i> alkaloids in optically active form or alternatively to the β-ketoester tetrahydro-β-carboline (THBC) unit <b>18</b>, by varying the equivalents of acid and the molar concentration. Attempts to utilize <b>18</b> to form the C(7)–C(16) bond of the akuammiline related alkaloids represented by strictamine (<b>22</b>), using metal-carbenoid chemistry, are also described