The anionic malonate-derived N-heterocyclic carbenes (maloNHCs) react cleanly and rapidly with copper chloride to generate the anionic complexes of type [(maloNHC)CuCl]·Li, which crystallize in the solid state either in an oligomeric trimer arrangement or in polymeric helixes depending on the substitution pattern and the solvent. Ten zwitterionic heteroleptic Cu(I) complexes combining the anionic maloNHC and a neutral imidazol-2-ylidene are also obtained in a very selective manner and fully characterized. Whereas the anionic complexes are relatively active catalysts for the hydrosilylation of carbonyl compounds, the zwitterionic complexes reveal to be efficient and extremely robust pre-catalysts for the intramolecular cyclopropanation reaction of a diazo ester and outperform the corresponding cationic Cu(i) complexes with classical imidazol-2-ylidenes.
We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist properties in the same molecule. We describe the structure-activity relationship that lead us to the promising derivative: N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine 16. The latter has high affinity for D2 and 5-HT1A receptors, whereas it possesses only a weak affinity for 5-HT2A sites. In cellular models of signal transduction, 16 behaves as a silent antagonist at rD2 receptors while activating h5-HT1A receptors with an efficacy at least equivalent to that of the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. These dual actions confer a unique pharmacological profile to the product. In a behavioral model predictive of positive symptoms, 16 has an activity comparable to that of the typical antipsychotic haloperidol, while it is devoid of cataleptogenic effects. Although it produces behaviors characteristic of 5-HT1A receptor activation in rats, these occur at doses 100 times higher than those with (+/-)-8-OH-DPAT. We believe that the relative balance of D2 and 5-HT1A actions in 16 is appropriate, possibly optimal, to ensure superior efficacy and tolerability over existing antipychotic drugs.
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