Synthesis, biological evaluation and structure–activity relationship of new GABA uptake inhibitors, derivatives of 4-aminobutanamides

• Published in: European journal of medicinal chemistry Vol. 83; pp. 256 - 273
• Main Authors: Kowalczyk, Paula, Sałat, Kinga, Höfner, Georg C., Mucha, Marta, Rapacz, Anna, Podkowa, Adrian, Filipek, Barbara, Wanner, Klaus T., Kulig, Katarzyna
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 18-08-2014
• Subjects: 4-Aminobutanamides; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Antidepressive Agents - chemical synthesis; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Chemistry Techniques, Synthetic; Depression; GABA uptake inhibitors; GABA Uptake Inhibitors - chemical synthesis; GABA Uptake Inhibitors - chemistry; GABA Uptake Inhibitors - pharmacology; GABA Uptake Inhibitors - therapeutic use; gamma-Aminobutyric Acid - chemical synthesis; gamma-Aminobutyric Acid - chemistry; gamma-Aminobutyric Acid - pharmacology; gamma-Aminobutyric Acid - therapeutic use; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Male; mGAT1–4; Mice; Motor Activity - drug effects; Pain; Pentylenetetrazole - adverse effects; Pilocarpine - adverse effects; Rotarod Performance Test; Seizures; Seizures - chemically induced; Seizures - drug therapy; Structure-Activity Relationship; Depression; 4-Aminobutanamides; Pain; mGAT1–4; GABA uptake inhibitors; Seizures
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.06.024

Six series of 2-substituted 4-aminobutanamide derivatives were synthesized and evaluated for their ability to inhibit GABA transport proteins mGAT1−4 stably expressed in HEK-293 cell lines. The pIC50 values determined were in the range 4.23–5.23. Two compounds (15b and 15c) were selected for further in vitro studies. These compounds were also subjected to preliminary behavioral studies to evaluate their anticonvulsant, antidepressant-like, and antinociceptive activities in mice. Their influence on motor coordination was also assessed. We report that, among a spectrum of in vivo activities, both 15b and 15c displayed significant activity against pentylenetetrazole (PTZ)-induced seizures.
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•The six series of 2-substituted 4-aminobutanamide derivatives were synthesized.•The compounds obtained were evaluated for ability to inhibit GABA transporters.•The pIC50 values determined were in the range 4.23–5.23.•Selected compounds were subjected to preliminary in vivo behavioral studies.