title: 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.
authors.affiliation: Research Foundation ITSUU Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukasawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Muratake
authors.forename: Ai
authors.initials: A
authors.lastname: Ito
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yohei
authors.initials: Y
authors.lastname: Amano
authors.forename: Marina
authors.initials: M
authors.lastname: Nagae
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D017646:Organosilicon Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects; D000069583:Pregabalin; D011597:Psychomotor Performance / Q000187:drug effects; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D014110:Touch; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000700:Analgesics; D017646:Organosilicon Compounds; C000595860:silagaba132; C000595861:silagaba161; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid
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