Recent developments in catalytic C-H amination are discussed in this feature article. The careful design of reagents and catalysts now provides efficient conditions for exquisitely selective intramolecular as well as intermolecular nitrene C-H insertion. The parallel emergence of C-H activation/amination reactions opens new opportunities complementary to those offered by nitrenes.

Benzodiazepines are widely used anxiolytics and anticonvulsants, and their potent sedative properties are routinely used in presurgical anaesthesia. However, they are also known to induce a strong anterograde amnesia in patients. Specific benzodiazepine antagonists have recently been described, some of which have intrinsic pharmacological properties that are opposite to those of benzodiazepines. These have been called inverse agonists and they have been shown to be proconvulsant or convulsant whereas benzodiazepines are anticonvulsants. Inverse agonists are also anxiogenic rather than anxiolytic. Since benzodiazepines induce anterograde amnesia, we have investigated the possibility that inverse agonists might also have an opposite effect for this property and so enhance acquisition (learning) and (or) retention (memory). We report here that, in three different animal models, an inverse agonist of the beta-carboline group, methyl beta-carboline-3-carboxylate (beta-CCM), enhances animal performance in three different tasks used to investigate learning and memory.

A three-dimensional model of the human extracellular Ca 2؉ -sensing receptor (CaSR) has been used to identify specific residues implicated in the recognition of two negative allosteric located in transmembranes (TM) 6 and TM7, in the binding pocket for both calcimimetics and calcilytics, despite important differences observed between each family of compounds. The TMs involved in the recognition of both calcilytics include residues located in TM3 (Arg-680 3.28 , Phe-684 3.32 , and Phe-688 3.36 ). However, our study indicates subtle differences between the binding of these two compounds. Importantly, the observation that some mutations that have no effect on calcimimetics recognition but which affect the binding of calcilytics in TM3 and TM5, suggests that the binding pocket of positive and negative allosteric modulators is partially overlapping but not identical. Our CaSR model should facilitate the development of novel drugs of this important therapeutic target and the identification of the molecular determinants involved in the binding of allosteric modulators of class 3 G-protein-coupled receptors.