Prelegent: prof. Karol Bruzik (Department of Pharmaceutical Sciences, University of Illinois at Chicago, USA)
Temat: GABA-A RECEPTOR AS TARGET OF CNS DRUGS - INTERSUBUNIT BINDING SITES SPECIFICITY OF ETOMIDATE AND BARBITURATES
Streszczenie: The ligand-gated ion-channel, human brain GABAA receptor, is a complex collection of 19 molecular species comprising hetero-pentamers of several a, b, g, d and other protein subunits. GABAA receptor is a macromolecular target of a large variety of popular CNS drugs that include general anesthetics, antiepileptics, anxiolytics, antidepressants and sedatives. Many of these drugs bind inside the specific interfaces that separate the various subunits, and most are positive allosteric modulators of GABA agonist action that affects ion-channel function of the receptor. I will provide a chemist's perspective on the inhibitory role of GABAA receptor in brain neural networks and its modulation by the allosteric ligands, as well as the current state-of-art in determining the location of binding sites of GABAA receptor ligands. Up until very recently, the paucity of structural data on the native brain receptor necessitated the use of photolabeling techniques combined with homology models based on simpler orthologs to determine the location and the makeup of the binding sites. The third part of this lecture series will consider the effect of barbiturates and etomidate on the GABAAR function. I will describe our efforts toward the design and synthesis of photolabeling probes of the two different binding sites located in ab, and bg subunit interfaces, their pharmacological characterization, location of the binding sites in the transmembrane domain, photoprobes' binding specificity and application for ligand screening. I will also discuss the effect of barbiturate structures on their anesthetic vs. convulsant activity. Finally, the synergism vs. additivity of pharmacological activity of these drugs binding at the disparate locations will be addressed. The synergy between the drugs will allow administration of lower doses of drug mixtures, resulting in lower undesired drug reactions and toxicity. All discussed results will be reconciled with the current state-of-art structural information from the cryo-EM method.
Data i godzina: 18.05.2022 (środa), godzina 13:30