Naturbasierende und synthetische Liganden für GABA A-Rezeptoren untersucht mittels zwei-Elektroden Spannungsklemme

Abstract

GABAA receptors are the most important inhibitory neurotransmitter receptors in the mammalian brain. These ionotropic ligand-gated ion-channels, which are targets of the neurotransmitter -aminobutric acid (GABA), also occur in the autonomic nervous system, various organs and immune system-cells. The major isoform of GABAA receptors is composed of two 1, two 2, and one 2 subunit. Nineteen subunits exist in mammal, giving rise to multiple receptor subtypes. Clinically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, inhalation and intravenous anaesthetics have been identi ed as GABAA receptor modulators. Diverse substances of natural origin can modulate GABA-induced currents in dierent GABAA receptor subtypes as well. Their physiological eects, like sleep-induction, have been observed for over thousands of years. In this work potential synthetic drug candidates as well as substances of plant origin were investigated for their modulatory eects on GABAA receptors and their possible subtype selectivity. The electrophysiological measurements were performed on GABAA receptors, expressed in oocytes from Xenopus laevis, by two-electrode-voltage-clamp method. At rst the eects of the synthetic pyrazoloquinolinone LAU 206 on receptor subtype 1 3 were reproduced in order to obtain experience in handling of the experimental setup. LAU 176, which has been found in previous studies to be most ecacious in 1 containing receptors, was then investigated for -selectivity in receptors and found to be selective. The plant derived substances falcarindiol and the structurally related compound notoincisol A, occuring in plants like water hemlock (Oenanthe crocata) or in the roots and rhizomes of Notopterygium incisum, respectively, were also studied. Falcarindiol was con rmed and notoincisol A was found to be positive modulators of several receptor subtypes. This thesis provided novel insights into the subtype pro les of pyrazoloquinolinones, and established notoincisol A as GABAA receptor modulator with comparable potency and ecacy as falcarindiol.