Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the α2-δ Protein

Schwarz, Jacob B.; Gibbons, Sian E.; Graham, Shelley R.; Colbry, Norman L.; Guzzo, Peter R.; Le, Van‐Duc; Vartanian, Mark G.; Kinsora, Jack J.; Lotarski, Susan M.; Li, Zheng; Dickerson, Melvin R.; Su, Ti‐Zhi; Weber, Mark L.; El‐Kattan, Ayman; Thorpe, Andrew; Donevan, Sean D.; Taylor, Charles P.; Wustrow, David

doi:10.1021/jm0491086

Cited by 43 publications

(20 citation statements)

References 30 publications

(72 reference statements)

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“…The present study demonstrates that a new GABA analog PD-217014, like gabapentin and pregabalin, inhibited [ 3 H]-gabapentin binding to pig cortical membranes in a concentration-dependent manner, indicating that this compound is a potent ligand to the ␣ 2 ␦ subunit of voltage-gated calcium channels. The calculated K i value (18 nmol/l) of PD-217014 was comparable to that of pregabalin reported in a previous paper [23] .…”

Section: Discussionsupporting

confidence: 88%

“…Affinity to the ␣ 2 ␦ subunit was determined by scintillation proximity assay (SPA) using a pig brain membrane preparation, as described previously [22,23] . Curve fitting and IC 50 values were calculated using a four-parameter, nonlinear regression equation from Prism 4.0 software (GraphPad, USA), while K i values were determined using previously determined K d values for pig (20 nmol/l) and the equation of Cheng and Prusoff [24] .…”

Section: ␣ 2 ␦ -Binding Assaymentioning

confidence: 99%

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Effect of a New α2δ Ligand PD-217014 on Visceral Hypersensitivity Induced by 2,4,6-Trinitrobenzene Sulfonic Acid in Rats

Ohashi¹,

Kawai²,

Ninomiya

et al. 2007

Pharmacology

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PD-217014, a new GABA analog (1α,3α,5α-3-aminomethyl-bicyclo[3.2.0]heptane-3-acetic acid), inhibited [³H]-gabapentin binding to α₂δ subunit of voltage-gated calcium channels in a concentration-dependent manner (K_i = 18 nmol/l). Oral treatment with PD-217014 significantly inhibited the visceral hypersensitivity induced by an intra-colonic injection of trinitrobenzene sulfonic acid in rats. The anti-hyperalgesic effect of PD-217014 increased in a dose-dependent manner, and reached a plateau level at 60 mg/kg p.o. The visceral analgesia produced by PD-217014 at 30 and 60 mg/kg p.o. correlated with blood concentrations within 4 h after dosing, and maximal efficacy was obtained 2 h after dosing when the maximal blood concentration was achieved at either dose. These results indicate that PD-217014 is a potent α₂δ ligand and possesses visceral analgesic activity.

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Section: Discussionsupporting

confidence: 88%

Section: ␣ 2 ␦ -Binding Assaymentioning

confidence: 99%

Effect of a New α2δ Ligand PD-217014 on Visceral Hypersensitivity Induced by 2,4,6-Trinitrobenzene Sulfonic Acid in Rats

Ohashi¹,

Kawai²,

Ninomiya

et al. 2007

Pharmacology

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show abstract

“…tract and distribution across blood-brain barrier) [3,4] • No evidence of interaction with GABAB receptor [20] • Inhibition of Ca 2+ currents via high-voltageactivated channels containing the 2 -1 subunit, leading in turn to reduced neurotransmitter release and attenuation of postsynaptic excitability [5][6][7][8][9][10] • The decreased Ca 2+ influx reduces excitatory aminoacid (ex: glutamate) release leading to decreased AMPA receptor activation and noradrenaline relase in the brain [97].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Gabapentin and Pregabalin for the Acute Post-operative Pain Management. A Systematic-narrative Review of the Recent Clinical Evidences

Dauri¹,

Faria

Gatti³

et al. 2009

CDT

143

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Background: Gabapentin and pregabalin inhibit Ca 2+ currents via high-voltage-activated channels containing the 2 -1 subunit, reducing neurotransmitter release and attenuating the postsynaptic excitability. They are antiepileptic drugs successfully used also for the chronic pain treatment. A large number of clinical trials indicate that gabapentin and pregabalin could be effective as postoperative analgesics. This systematic-narrative review aims to analyse the most recent evidences regarding the effect of gabapentinoids on postoperative pain treatment.Methods: Medline, The Cochrane Library, EMBASE and CINHAL were searched for recent (2006)(2007)(2008)(2009) randomized clinical trials (RCTs) of gabapentin-pregabalin for postoperative pain relief in adults. Quality of RCTs was evaluated according to Jadad method. Visual analogue scale (VAS), opioid consumption and side-effects (nausea, vomiting, dizziness and sedation) were considered the most important outcomes.Results: An overall of 22 gabapentin (1640 patients), 8 pregabalin (707 patients) RCTs and seven meta-analysis were involved in this review. Gabapentin provided better post-operative analgesia and rescue analgesics sparing than placebo in 6 of the 10 RCTs that administered only pre-emptive analgesia. Fourteen RCTs suggested that gabapentin did not reduce PONV when compared with placebo, clonidine or lornoxicam. Pregabalin provided better post-operative analgesia and rescue analgesics sparing than placebo in two of the three RCTs that evaluated the effects of pregabalin alone vs placebo. Four studies reported no pregabalin effects on preventing the PONV. Conclusion:Gabapentin and pregabalin reduce pain and opioid consumption after surgery in confront with placebo, but comparisons with other standard post-operative regimens are not sufficient. Gabapentin and pregabalin seem not to have any influence on the prevention of PONV.

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“…One of these compounds, compound 34 which did not bind to the system L-amino acid transporter, had an anticonvulsant effect in vivo when given intracerebroventricularly but not orally (103). Therefore, the Lamino acid transporter may be important for the active transport of gabapentin through the blood-brain barrier or intestinal absorption but may not be directly involved in its cellular actions.…”

Section: -3 Gabapentin and System L-amino Acid Transportermentioning

confidence: 99%

“…Synthetic analogues of gabapentin with high binding affinity at the α 2 δ subunit have been developed and shown to have anticonvulsant and antinociceptive activities in vivo (103,105,131,132). However, the functional consequence of gabapentin binding to the α 2 δ subunit is still not well established.…”

Section: -4-4 Voltage-dependent Camentioning

confidence: 99%

Mechanisms of the Antinociceptive Action of Gabapentin

2006

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Abstract. Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA B receptors consisting of GABA B1a and GABA B2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K + channels, activating hyperpolarization-activated cation channels, and modulating Ca 2+ current by selectively binding to the specific binding site of [3 H]gabapentin, the α 2 δ subunit of voltage-dependent Ca 2+ channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the α 2 δ subunit of spinal N-type Ca 2+ channels is very likely the analgesic action target of gabapentin.

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Novel Cyclopropyl β-Amino Acid Analogues of Pregabalin and Gabapentin That Target the α₂-δ Protein

Cited by 43 publications

References 30 publications

Effect of a New α<sub>2</sub>δ Ligand PD-217014 on Visceral Hypersensitivity Induced by 2,4,6-Trinitrobenzene Sulfonic Acid in Rats

Effect of a New α<sub>2</sub>δ Ligand PD-217014 on Visceral Hypersensitivity Induced by 2,4,6-Trinitrobenzene Sulfonic Acid in Rats

Gabapentin and Pregabalin for the Acute Post-operative Pain Management. A Systematic-narrative Review of the Recent Clinical Evidences

Mechanisms of the Antinociceptive Action of Gabapentin

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