(R)- and (S)-4-Amino-3-(trimethylsilyl)methylbutanoic acids ameliorate neuropathic pain without central nervous system-related side effects

Muratake, Hideaki; Ito, Ai; Toda, Takahiro; Suzuki, Hideyuki; Fukasawa, Hiroshi; Tsuda, Makoto; Inoue, Kazuhide; Sugiyama, Kiyoshi; Shudo, Koichi

doi:10.1016/j.bmcl.2012.10.001

Cited by 5 publications

(13 citation statements)

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“…Each compound was orally administered at 30 mg/kg by gavage. As we previously found in SNL rats, 11 silagaba121 and 122 significantly increased the pain thresholds of SNL mice: that is, they are antiallodynic (Figure 2C). The ( S )-isomer, silagaba122, was more effective than the ( R )-isomer, silagaba121.…”

Section: Resultssupporting

confidence: 84%

“…We previously reported that pregabalin showed bilateral hypalgesic activity, increasing the pain thresholds on both sides of SNL rats at later time after administration, whereas silagaba121 and 122 increased the pain thresholds only on the ipsilateral operated side. 11 Silagaba131 and 132 showed similar antiallodynic efficacy in the ipsilateral paws (Figure 3A,B). In contrast to the results in SNL mice, however, silagaba131 did not increase the pain threshold in contralateral nonoperated paws, and therefore silagaba131 and 132 were not hypalgesic in SNL rats.…”

Section: Resultsmentioning

confidence: 73%

“…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.…”

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confidence: 99%

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

Fukasawa

Muratake

Ito

et al. 2014

ACS Chem. Neurosci.

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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.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 73%

mentioning

confidence: 99%

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

Fukasawa

Muratake

Ito

et al. 2014

ACS Chem. Neurosci.

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“…13,14) In our previous work, we evaluated the analgesic action of novel GABA derivatives containing silicon-carbon bonds and pregabalin in the PSL model (so-called Seltzer model) and the SNL model (so-called Chung model). 10,15) In those studies, we found that orally administered pregabalin significantly increased the withdrawal threshold not only on the ipsilateral operated side (anti-allodynic effect), but also on the contralateral nonoperated side. This increase of pain threshold on the contralateral side, which was observed with a delay compared to the ipsilateral side, can be considered as representing hypoalgesic action due to excessive sedative action on the pain-related higher centers after distribution of pregabalin into the brain.…”

Section: Resultsmentioning

confidence: 99%

Transdermal Administration of Aqueous Pregabalin Solution as a Potential Treatment Option for Patients with Neuropathic Pain to Avoid Central Nervous System-Mediated Side Effects

Fukasawa

Muratake

Nagae

et al. 2014

Biological & Pharmaceutical Bulletin

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Pregabalin, (S)-3-isobutyl-γ-aminobutyric acid (GABA), is a widely used adjuvant therapy for patients with neuropathic pain, which is defined as chronic pain caused by lesions or diseases of the somatosensory nervous system. However, dizziness and somnolence (sleepiness) are common dose-limiting side effects, probably due to excessive sedative effects on higher centers of the central nervous system (CNS) which are involved in the anticonvulsant and analgesic actions of pregabalin. We speculated that transdermal delivery would minimize centrally mediated side effects. To test this idea, we evaluated the analgesic effects of pregabalin delivered through the transdermal route in animal models of neuropathic pain. Transdermally administered pregabalin increased the pain thresholds in response to mechanical stimuli in a partial sciatic nerve ligation model in rats and a spinal nerve ligation model in mice, and surprisingly also in normal animals. It is noteworthy that simple transdermal application of an aqueous solution of pregabalin is effective. This could be a useful treatment option to avoid or minimize the CNS-mediated side effects of orally administered pregabalin.Key words neuropathic pain; pregabalin; transdermal administration Neuropathic pain is chronic pain caused by lesion or disease of the somatosensory nervous system. 1-3) It is characterized by allodynia (pain in response to normally innocuous stimuli), hyperalgesia (increased pain evoked by noxious stimuli) and spontaneous pain. Treatment of neuropathic pain remains a clinical challenge, because the pathophysiology of neuropathic pain is complex and the underlying mechanisms remain poorly understood. 4,5) Although chronic neuropathic pain often responds unsatisfactorily to opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), it can be treated effectively with antidepressants and antiepileptics as adjuvant analgesics. 5) The (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), pregabalin, which was identified as an antiepileptic in the early 1990's, is now widely used for treatment of diabetic peripheral neuropathy, postherpetic neuralgia, spinal cord injury nerve pain, fibromyalgia and partial onset seizures. 6-8) Unfortunately, though, central nervous system (CNS)-mediated side effects such as dizziness and somnolence (sleepiness) are common in pregabalin-treated patients and have a significant impact on their quality of life. 9) Therefore, other treatment options that overcome these problems would provide substantial benefits to patients. Topical application through the transdermal route is one possible option to reduce systemic drug exposure and penetration into the brain, and thereby to minimize CNS-mediated side effects. In this study, therefore, we evaluated the analgesic effects of transdermally administered pregabalin in rats and mice. MATERIALS AND METHODSChemicals Pregabalin (free base) used for experiments in rats was obtained from Sequoia Research Products Ltd. (Pangbourne, U.K.). Pregabalin (crystallized free base) used for experim...

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“…Pregabalin causes dizziness and had hypalgesic effects that were not observed in rats dosed with 158 and 159 . These results suggest that silicon analogs 158 and 159 can be considered as pregabalin analogs with reduced CNS side effects …”

Section: Silicon-containing Amino Acidsmentioning

confidence: 99%

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

2017

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In order to optimize a lead molecule for further development, bioisosteric replacements are generally adopted as one of the strategies. Silicon appears to be the right choice as a carbon isostere because of the similarity in chemical properties. Silicon can be strategically introduced in a molecule to modulate its druglike properties, providing medicinal chemists with an unconventional strategy for replacing a carbon atom. Silicon can also be introduced to replace other heteroatoms and can act as a surrogate of functional groups such as olefin and amide as well. The present Perspective focuses on the opportunities that silicon incorporation offers in drug discovery, with an emphasis on case studies where introduction of silicon has created a benefit over its analog. We have tried to highlight all the recent developments in the field and briefly discuss the challenges associated with them.

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(R)- and (S)-4-Amino-3-(trimethylsilyl)methylbutanoic acids ameliorate neuropathic pain without central nervous system-related side effects

Cited by 5 publications

References 12 publications

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

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

Transdermal Administration of Aqueous Pregabalin Solution as a Potential Treatment Option for Patients with Neuropathic Pain to Avoid Central Nervous System-Mediated Side Effects

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

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