Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression.

BACKGROUND: Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. METHODS: For pharmacological tests tiagabine was administered intraperitoneally 60 min before the assay. Behavioral tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic-like properties were evaluated using the four plate test and the elevated plus maze test. Antidepressant-like activity was assessed in the forced swim test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals' locomotor activity and motor coordination was investigated, too. RESULTS: Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% (p<0.01), but it had no activity in the maximal electroshock seizure test. Tiagabine showed anxiolytic-like and antidepressant-like effects. Although it apparently reduced animals' nociceptive responses in pain tests, these activities rather resulted from its sedative and motor-impairing properties demonstrated in the locomotor activity and the rotarod tests, respectively. CONCLUSIONS: The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders.

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

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.

New investigational drugs for the treatment of neuropathic pain.

INTRODUCTION: Neuropathic pain (NP) is a chronic condition that arises from a lesion or dysfunction of the somatosensory nervous system. However, there are several new targets and novel technologies in the pipeline to address this unmet medical need. AREAS COVERED: In this review, the authors briefly discuss a direction of the development of agents that could be potentially used in NP treatment. Special attention is paid to 1.7-selective voltage-gated sodium channels, N-type voltage-gated calcium channels, angiotensin II (Ang II) AT2 receptors and nerve growth factor (NGF) as promising targets for new drugs. Furthermore, the article also presents and discusses, in detail, the results of Phase II clinical studies with the AT2 receptor antagonist - EMA401 in NP (the results of Phase II clinical trials of other described compounds are not available, yet). EXPERT OPINION: There is a real hope that new drugs for NP may be available soon. This hope is based on advancing methods of genomics, developing new targets and more efficient drug screening. Some forms of direct influence on voltage-gated ion channels have a place in the treatment of NP, while the development of entirely novel Ang II AT2 receptor antagonists or NGF inhibitors may be available for many chronic pain sufferers in the foreseeable future.

2-Substituted 4-hydroxybutanamides as potential inhibitors of γ-aminobutyric acid transporters mGAT1-mGAT4: synthesis and biological evaluation.

A series of 2-substituted 4-hydroxybutanamide derivatives has been synthesized by the aminolysis of appropriate 2-substituted dihydrofuran-2(3H)-one derivatives with various substituted benzylamines. The final compounds have been evaluated for their capability of inhibiting the GABA transport proteins GAT1-4 stably expressed in HEK-239 cell lines. The pIC50 values determined were in the range 4.21-5.14. Two compounds (16a and 16d), which displayed the most interesting profiles in in vitro tests, have also been subjected to further preliminary behavioral studies, evaluating their antinociceptive activity in hot-plate, writhing, and formalin tests. Their influence on motor coordination has also been assessed.