Design, Synthesis, and Pharmacological Evaluation of Novel β2/3 Subunit-Selective γ-Aminobutyric Acid Type A (GABAA) Receptor Modulators.

Abstract

Subunit-selective modulation of γ-aminobutyric acid type A receptors (GABAAR) is considered to exert fewer side effects compared to unselective clinically used drugs. Here, the β2/3 subunit-selective GABAAR modulators valerenic acid (VA) and loreclezole (LOR) guided the synthesis of novel subunit-selective ligands with simplified structures. We studied their effects on GABAARs expressed in Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Five compounds showed significantly more efficacious modulation of GABA-evoked currents than VA and LOR with retained potency and selectivity. Compound 18 [( E)-2-Cyano-3-(2,4-dichlorophenyl)but-2-enamide] induced the highest maximal modulation of GABA-induced chloride currents ( Emax: 3114 ± 242%), while 12 [( Z)-3-(2,4-dichlorophenyl)but-2-enenitrile] displayed the highest potency (EC50: 13 ± 2 μM). Furthermore, in hippocampal neurons 12 facilitated phasic and tonic GABAergic inhibition, and in vivo studies revealed significantly more potent protection against pentylenetetrazole (PTZ)-induced seizures compared to VA and LOR. Collectively, compound 12 constitutes a novel, simplified, and subunit-selective GABAAR modulator with low-dose anticonvulsant activity.

• Authors: Marco Stadler, Serena Monticelli, Thomas Seidel, Denise Luger, Isabella Salzer, Stefan Boehm, Wolfgang Holzer, Christoph Schwarzer, Ernst Urban, Sophia Khom, Thierry Langer, Vittorio Pace, Steffen Hering
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 1 Pg. 317-341 (01 10 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30289721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Anticonvulsants
• Indenes
• Protein Subunits
• Receptors, GABA-A
• Sesquiterpenes
• Triazoles
• valerenic acid
• loreclezole
• dopastin
• Pentylenetetrazole

Topics

• Amides (chemistry, metabolism, therapeutic use)
• Animals
• Anticonvulsants (chemical synthesis, metabolism, therapeutic use)
• Drug Design
• Female
• Hippocampus (metabolism)
• Indenes (chemistry)
• Oocysts (metabolism)
• Patch-Clamp Techniques
• Pentylenetetrazole (toxicity)
• Protein Subunits (chemistry, metabolism)
• Receptors, GABA-A (chemistry, genetics, metabolism)
• Seizures (chemically induced, drug therapy, pathology)
• Sesquiterpenes (chemistry)
• Structure-Activity Relationship
• Triazoles (chemistry)
• Xenopus laevis (metabolism)