Synthesis of natural compounds for GABAA receptor modulation

-Aminobutyric acid type A (GABAA ) receptors mediate the inhibitory neurotransmission in the brain. They have a pentameric structure consisting of a(1-6), ß(1-3), (1-3), d, e, (1-3), p and T subunits. GABA A receptors moderate the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions. Enhancement of GABA A receptor-mediated synaptic inhibition represents the basis for the pharmacotherapy of various neurological and psychiatric disorders. Therefore, GABAA receptors provide key drug targets. Two non-cytotoxic NPs derived from medicinally used plants, valerenic acid (VA, from Valerian root) and honokiol (a constituent of Magnolia officinalis) were recently identified as subunit-specific positive modulators of GABA A receptors. Pharmacological studies suggest that VA and honokiol are useful starting templates for synthesis of optimized lead structures. VA selectively modulates GABA A receptors comprising a ß2 or ß3 subunit, while honokiol has been shown to be more efficient on receptors containing a3 subunits. The ß2/ß3 specificity indicates possible antiepileptic and/or general anaesthetic action of VA while honokiol and its derivatives are expected to induce predominantly anxiolysis and less sedation. In general, natural products (NP) play a dominant role in the discovery of leads for drug development. A major obstacle to NP chemistry is the continuous supply of larger amounts required for the synthesis of derivatives and for pharmacological studies. Sometimes, interesting analogs are not accessible via derivatization of the natural compound. Therefore, we aim for a de novo total synthesis of VA that will allow the design of VA-derivatives for structure activity studies on GABA A receptors. For honokiol, we first intend to synthesize GABA A ligands with a wide array of functional groups and structural variations in side chains and core. Their structure-activity- relationship will reveal particularly promising candidates for further optimization. The synthetic approach toward VA and honokiol and their derivatives will meet the need for a suitably diverse library of ligands. Additionally, it will serve in the optimization of potential lead compounds and increase the quantities available for pharmacological studies.

?-Aminobutyric acid (GABA) is the principle inhibitory neurotransmitter in the mammalian brain. GABA is present in 20-50 % of the cerebral cortex synapses. Dysfunction of the GABAergic system is associated with a multitude of neurological disorders including insomnia, anxiety, panic and mood disorders, alcoholism and epilepsy. A promising biological target are GABAA channels which are modulated by numerous structurally distinct substances including clinically important drugs as BZDs, barbiturates and various general anaesthetics, but also by several compounds of plant origin, including flavonoids. Thus, valerenic acid (VA) and honokiol (HK) have recently been shown to selectively modulate GABAA receptor subtypes. Thus the aim of the project was the total synthesis and biological testing of VA and HK and derivatives thereof to obtain lead structures for later drug development. In a five year cooperation between the Institute of Pharmaceutical Science at Uni Graz W. Schühly), the Department of Pharmacology at Uni Vienna (S. Hering) and the institute of Organic Chemistry at Uni Vienna (J Mulzer) about 100 VA- and HK-derivatives have been synthesized by the Mulzer and the Schühly groups and subjected to electrophysiological cell tests and later mouse experiments by the Hering group. In the end some promising drug candidates have been identified which have some advantages over the parent natural compounds: