RESUMO
Ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype play a key role in synaptic plasticity representing one of the mechanisms for learning and memory formation. They can also serve as targets for the development of novel classes of pharmaceuticals for the treatment or substantive correction of many serious neurodegenerative and psychoneurological disorders. The search and studies of various types of AMPA receptor ligands attract considerable attention from academic organizations and pharmaceutical companies all over the world. This review mainly focuses on recent advances in this field. The architecture and operational mechanism of the receptor as well as its major binding sites and ligand types are considered. Special attention is paid to the studies of mechanisms of action and novel chemotypes of AMPA receptor agonists and competitive antagonists, positive and negative allosteric modulators, auxiliary protein-dependent allosteric modulators, and ion channel blockers.
Assuntos
Ácido Glutâmico , Receptores de AMPA , Ligantes , Receptores de Glutamato , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiônicoRESUMO
A new derivative of 3,7-diazabicyclo[3.3.1]nonane, which showed a high activity as a positive allosteric modulator of AMPA receptors of the CNS, was studied in electrophysiological experiments. At doses of 0.01 mg/kg, this compound significantly improved the memory of experimental animals disturbed by maximal electric shock. The results indicate that this compound is a promising candidate for preclinical trials and clinical studies as a drug for treatment of a number of psychoneurological diseases.
Assuntos
Hipocampo/metabolismo , Transtornos Mentais , Doenças do Sistema Nervoso , Nootrópicos , Receptores de AMPA , Regulação Alostérica , Animais , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Nootrópicos/química , Nootrópicos/farmacologia , Ratos , Receptores de AMPA/agonistas , Receptores de AMPA/química , Receptores de AMPA/metabolismoRESUMO
A positive allosteric modulator of AMPA receptors has been designed using computer-aided molecular modeling techniques. It possessed a record high experimentally confirmed potency in the picomolar concentration range and belongs to a new type of bivalent AMPA receptor ligands containing bicyclo[3.3.1]nonane scaffold. The suggested structure could serve as a basis for further optimization and development of drugs for the treatment of neurodegenerative diseases, cognition enhancement, and improvement of memory.
