Silicon-Containing GABA Derivatives, Silagaba Compounds, as Orally Effective Agents for Treating Neuropathic Pain without Central-Nervous-System-Related Side Effects
ABSTRACT Neuropathic pain is a chronic condition resulting from neuronal damage. Pregabalin, the (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), is widely used to treat neuropathic pain, despite the occurrence of central nervous system (CNS)-related side effects such as dizziness and somnolence. Here we describe the pharmacology of novel GABA derivatives containing silicon-carbon bonds, silagaba compounds. Silagaba131, 132 and 161 showed pregabalin-like analgesic activities in animal models of neuropathic pain, but in contrast to pregabalin, they did not impair neuromuscular coordination in rotarod tests. Pharmacokinetic studies showed that brain exposure to silagaba compounds was lower than that to pregabalin. Surprisingly, despite their potent analgesic action in vivo, silagaba compounds showed only weak binding to α2-δ protein. These compounds may be useful to study mechanisms of neuropathic pain. Our results also indicate that silagaba132 and 161 are candidates for orally effective treatment of neuropathic pain without CNS-related side effects.
SourceAvailable from: iranneurology.org[Show abstract] [Hide abstract]
ABSTRACT: Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Examples of neuropathic pain include painful polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain. Clinically, neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Methods such as questionnaires for screening and assessment focus on the presence and quality of neuropathic pain. Basic research is enabling the identification of different pathophysiological mechanisms, and clinical assessment of symptoms and signs can help to determine which mechanisms are involved in specific neuropathic pain disorders. Management of neuropathic pain requires an interdisciplinary approach, centred around pharmacological treatment. A better understanding of neuropathic pain and, in particular, of the translation of pathophysiological mechanisms into sensory signs will lead to a more effective and specific mechanism-based treatment approach.The Lancet Neurology 08/2010; 9(8):807-19. DOI:10.1016/S1474-4422(10)70143-5 · 21.82 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.Mayo Clinic Proceedings 03/2010; 85(3 Suppl):S3-14. DOI:10.4065/mcp.2009.0649 · 5.81 Impact Factor
Journal of Medicinal Chemistry 08/1991; 34(7):2295-8. DOI:10.1021/jm00111a053 · 5.48 Impact Factor