RESUMEN
Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.
Asunto(s)
Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Antipsicóticos/química , Antipsicóticos/clasificación , Sitios de Unión , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Ratones , Modelos Moleculares , Estructura Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
The new germacrane derivatives ketopelenolides C and D have been isolated from great mugwort (Artemisia arborescens). Their stereostructure elucidation exemplifies some of the most common pitfalls facing the configurational assignment of medium-sized polyfunctionalized compounds. It was established through a combined strategy including chemical derivatization, NMR data analysis, molecular modeling, and quantum-mechanical calculations including a comparison between experimental 13C NMR data and a Boltzmann-weighted average of DFT-calculated 13C NMR chemical shifts.