Silicon-Containing GABA Derivatives, Silagaba Compounds, as Orally Effective Agents for Treating Neuropathic Pain without Central-Nervous-System-Related Side Effects

Neuropathic pain is a chronic condition resulting from damage or dysfunction in the peripheral and/or central nervous system. Treatment of neuropathic pain is still a challenge, because the pathophysiology is complex and the underlying mechanism remains poorly understood.1 Chronic pain often responds unsatisfactorily to opioids and nonsteroidal anti-inflammatory drugs. However, adjuvant analgesics, including antidepressants and antiepileptics, are effective.2 The S-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), pregabalin [(S)-1], which was reported in the early 1990s as a novel antiepileptic, is widely used for treatment of diabetic peripheral neuropathy, postherpetic neuralgia, neuropathic pain following spinal cord injury, fibromyalgia, and also partial-onset seizures,3−5 although dizziness and somnolence (sleepiness) are common side effects.6 The higher incidence of these side effects in elderly patients, which may be due to age-related decrease of renal clearance, sometimes has a significant impact on quality of life. Thus, there is a significant unmet need for an orally effective analgesic without central nervous system (CNS)-mediated side effects to treat neuropathic pain. The specific binding of pregabalin to the α2-δ subunit of voltage-gated calcium channel, which is expressed at presynaptic terminals of neurons in the spinal cord and brain, is thought to be responsible for its analgesic and anticonvulsant actions.5,7,8 Sites of dense α2-δ expression in the brain include the insula and the cingular cortex, which are involved pain-encoding, partial epilepsy, vestibular sensation, and also sleep stages.5,9 Excessive sedative effect of pregabalin in these areas may result in dizziness and somnolence. Previously, we reported the synthesis of (R)- and (S)-isomers of 4-amino-3-(trimethylsilyl)methylbutanoic acid, designated as silagaba121 [(R)-2a] and silagaba122 [(S)-2a], respectively, and we evaluated their analgesic efficacy in a spinal nerve ligation (SNL) model, the so-called Chung model, in rats.10,11 In SNL rats, pregabalin showed CNS-mediated hypalgesic effects, as indicated by an increase of the normal pain threshold on the nonoperated side. Silagaba121 and 122 did not show such hypalgesic effects, and appear to be candidates for orally effective analgesics without CNS-mediated side effects. Here, we synthesized a series of silagaba derivatives and evaluated their analgesic effects. The results of rotarod tests and pharmacokinetic studies were consistent with the absence of CNS-mediated effects of these compounds.