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L. Wimmer, A. Schöffmann, S. Pakfeifer, D. Schönbauer, S. Khom, T. Schwarz, T. Erker, S. Hering, M.D. Mihovilovic:
"Synthesis of piperine analogs as GABAA receptor ligands";
Poster: 16th Tetrahedron Symposium, Berlin; 16.06.2015 - 19.06.2015.

Black pepper is traditionally used in Asian folk medicine as antiepileptic, antianxiety, sedative, and sleep inducing preparation. One of the ingredients of piper nigrum, its natural pungent alkaloid piperine, was recently identified as a positive allosteric modulator of the major inhibitory neurotransmitter receptors GABAA in the brain.1 Drugs enhancing chloride currents through GABAA receptors play an important role in the treatment of general anxiety, panic disorders, sleep disturbances, and epilepsy.2 The present study is dedicated to the optimization of the piperine scaffold in terms of ligand potency and receptor subtype selectivity. Compounds were tested for GABAA receptor activity using a two-electrode voltage clamp assay on Xenopus laevis oocytes. The target molecule (Fig. 1) was divided into three distinct structural motifs: amide, linker region and the aryl moiety. In an early stage of the project the amide functionality was modified.
Based on the gained knowledge, modifications of the double bond system, the linker region, was approached.3 Hence by applying transition metal catalyzed cross coupling reactions, derivatives with a rigidified linker region were synthesized.
Further modifications of the aryl-moiety were performed by a palladium-catalyzed Heck cross-coupling reaction of conjugated dienamides.4 This reaction strategy served as a highly modular platform for library synthesis.
Biological testing revealed several potential hit compounds with up to 5-fold increased efficacy and one particular compound (LAU399) was found to be functionally selective for β2/3-containing receptors, indicating non-sedative anxiolytic properties.

Piperine, GABAA, anxiolytic