Identification of Novel Ligands for the Gabapentin Binding Site on the α<sub>2</sub>δ Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents

Bryans, Justin S.; Davies, Natasha; Gee, N S; Dissanayake, Visaka U.K.; Ratcliffe, Giles S.; Horwell, David C.; Kneen, Clare O.; Morrell, Andrew I.; Oles, Ryszard J.; O’Toole, J. C.; Perkins, Gemma M.; Singh, Lakhbir; Suman‐Chauhan, N.; O'Neill, Jacqueline A.

doi:10.1021/jm970649n

Cited by 84 publications

(54 citation statements)

References 16 publications

(31 reference statements)

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“…It has been hypothesized that this antinociceptive action may be due to binding to the ␣ 2 ␦ subunit of voltagegated calcium channels, resulting in inhibition of calcium currents and neurotransmitter release (Gee et al, 1996;Fink et al, 2000;Maneuf and McKnight, 2001;Sutton et al, 2002). The synthesis of GBP analogs with varying affinities for ␣ 2 ␦ has provided an additional strategy to examine the role of ␣ 2 ␦ in the antinociceptive action of GBP (Bryans et al, 1998). Using this approach, Field et al (2000) evaluated the antiallodynic efficacy of two stereoisomers displaying stereoselective binding to ␣ 2 ␦: (1S,3R)3-MeGBP (IC 50 ϭ 42 nM) and (1R,3R)3-MeGBP (IC 50 Ͼ 10,000 nM).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Urban¹,

Ren²,

Park³

et al. 2005

J Pharmacol Exp Ther

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The anticonvulsant gabapentin (GBP) has been shown effective for the treatment of neuropathic pain, although its mechanism of action remains unclear. A recent report has suggested that binding to the ␣ 2 ␦ subunit of voltage-gated calcium channels contributes to its antinociceptive effect, based on the stereoselective efficacy of two analogs: (1S,3R)3-methylgabapentin (3-MeGBP) (IC 50 ϭ 42 nM), which is effective in neuropathic pain models; and (1R,3R)3-MeGBP (IC 50 Ͼ 10,000 nM), which is ineffective (Field et al., 2000). The present study was designed to further examine the profiles of GBP and 3-MeGBP in rat models of acute and persistent pain. Systemic administration of GBP or (1S,3R)3-MeGBP inhibited tactile allodynia in the spinal nerve ligation model of neuropathic pain, whereas (1R,3R)3-MeGBP was ineffective. The antiallodynic effect of GBP, but not (1S,3R)3-MeGBP, was blocked by i.t. injection of the GABA B receptor antagonist [3-[[(3,4-Systemic GBP or (1S,3R)3-MeGBP also inhibited the second phase of formalin-evoked nociceptive behaviors, whereas (1R,3R)3-MeGBP was ineffective. However, both (1S,3R)3-MeGBP and (1R,3R)3-MeGBP, but not GBP, inhibited first phase behaviors. In the carrageenan model of inflammatory pain, systemic GBP or (1R,3R)3-MeGBP failed to inhibit thermal hyperalgesia, whereas (1S,3R)3-MeGBP had a significant, albeit transient, effect. Systemic (1S,3R)3-MeGBP, but not GBP or (1R,3R)3-MeGBP, also produced an antinociceptive effect in the warm water tail withdrawal test of acute pain. These data demonstrate that GBP and 3-MeGBP display different antinociceptive profiles, suggesting dissimilar mechanisms of antinociceptive action. Thus, the stereoselective efficacy of 3-MeGBP, presumably related to ␣ 2 ␦ binding, likely does not completely account for the mechanism of action of GBP.Gabapentin (GBP; Neurontin) is an anticonvulsant that has found increased utility for the treatment of clinical neuropathic pain. Although originally developed for the treatment of spasticity and epilepsy, recent attention has focused on the utility of GBP for the treatment of neuropathic pain based on its efficacy and minimal side-effect profile in clinical trials (Rice and Maton, 2001). In rodent neuropathic pain models, GBP effectively attenuates thermal and mechanical hypersensitivity following peripheral nerve ligation (Xiao and Bennett, 1996;Hunter et al., 1997;Hwang and Yaksh, 1997). GBP has also been shown to inhibit thermal and mechanical hyperalgesia following carrageenan-induced inflammation (Field et al., 1997b;Lu and Westlund, 1999); however, other studies have reported limited effectiveness of GBP for inflammatory pain (Gould et al., 1997;Patel et al., 2001). Additionally, GBP inhibits spontaneous nociceptive behaviors and mechanical hyperalgesia produced by intraplantar formalin or surgical incision, respectively (Field et al., 1997a,b). The antinociceptive effects of GBP in models of neuropathic, inflammatory, and surgical pain appear to be selective for injury-induced hypersensitivity, ...

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Section: Discussionmentioning

confidence: 99%

Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Urban¹,

Ren²,

Park³

et al. 2005

J Pharmacol Exp Ther

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“…Hence, gabapentin may not have to enter nerve terminal or cells via L-amino acid transporter, which was supported by our results. The 2 subunit of voltage-sensitive calcium channels has been suggested as the binding site of gabapentin (8). However, electrophysiological studies did not exhibit an action of gabapentin on voltage-sensitive calcium channels (25).…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that gabapentin may alter the facilitated state and the major site of action of gabapentin may be the spinal cord. Although the mechanisms of action of gabapentin are not clear, the relations to specific receptors (1, 2) or substances (6), L-amino acid transporter (7), or voltage-dependent calcium channel (8) has been proposed as the sites of action of gabapentin.…”

Section: Introductionmentioning

confidence: 99%

Spinal Gabapentin and Antinociception: Mechanisms of Action

2003

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Spinal gabapentin has been known to show the antinociceptive effect. Although several assumptions have been suggested, mechanisms of action of gabapentin have not been clearly established. The present study was undertaken to examine the action mechanisms of gabapentin at the spinal level. Male SD rats were prepared for intrathecal catheterization. The effect of gabapentin was assessed in the formalin test. After pretreatment with many classes of drugs, changes of effect of gabapentin were examined. General behaviors were also observed. Intrathecal gabapentin produced a suppression of the phase 2 flinching, but not phase 1 in the formalin test. The antinociceptive action of intrathecal gabapentin was reversed by intrathecal NMDA, AMPA, D-serine, CGS 15943, atropine, and naloxone. No antagonism was seen following administration of bicuculline, saclofen, prazosin, yohimbine, mecamylamine, L-leucine, dihydroergocristine, or thapsigargin. Taken together, intrathecal gabapentin attenuated only the facilitated state. At the spinal level, NMDA receptor, AMPA receptor, nonstrychnine site of NMDA receptor, adenosine receptor, muscarinic receptor, and opioid receptor may be involved in the antinociception of gabapentin, but GABA receptor, L-amino acid transporter, adrenergic receptor, nicotinic receptor, serotonin receptor, or calcium may not be involved.

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“…Nonstrychnine site of NMDA receptor and the 2 subunit of voltage-sensitive calcium channels have been suggested as the binding site of gabapentin (4,5,13). Clinically, the most common side effects of gabapentin are dizziness, somnolence, headache, and diarrhea (12).…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic Effects of Gabapentin in Rats

Yoon

Choi

2003

J Korean Med Sci

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Gabapentin has been known to elicit the antinociceptive effect. However, little has been known about the effect of gabapentin on the cardiovascular system. The author's aim of this experiment was to examine the hemodynamic effects of gabapentin. Male Sprague-Dawley rats were used. Intrathecal or intracerebroventricular catheters were implanted and gabapentin was delivered through each catheter or directly into the peritoneal cavity. For hemodynamic measurements, catheters were inserted into the tail artery. Blood pressure and heart rate were measured over 60 min following administration of gabapentin. Intrathecal and intraperitoneal gabapentin did not induce significant changes of hemodynamics over the 60 min compared to the baseline value. Intracerebroventricular gabapentin increased systolic and diastolic blood pressure, but there is no statistically difference in blood pressure change according to the dose.

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Identification of Novel Ligands for the Gabapentin Binding Site on the α₂δ Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents

Cited by 84 publications

References 16 publications

Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Spinal Gabapentin and Antinociception: Mechanisms of Action

Hemodynamic Effects of Gabapentin in Rats

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Identification of Novel Ligands for the Gabapentin Binding Site on the α2δ Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents

Cited by 84 publications

References 16 publications

Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Spinal Gabapentin and Antinociception: Mechanisms of Action

Hemodynamic Effects of Gabapentin in Rats

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Product

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Identification of Novel Ligands for the Gabapentin Binding Site on the α₂δ Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents