Phenytoin differentially modulates the affinity of agonist and antagonist ligands for σ<sub>1</sub> receptors of guinea pig brain

Cobos, Enrique J.; Baeyens, José M.; Pozo, Esperanza Del

doi:10.1002/syn.20103

Cited by 68 publications

(68 citation statements)

References 17 publications

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“…As expected, the known s 1 antagonist BD-1063 inhibited [ 3 H](1)-pentazocine specific binding in a concentration-dependent manner, with an IC 50 value of 40.21 6 3.24 nM. This value was similar to that found in previous studies (Entrena et al, 2009a;Cobos et al, 2005Cobos et al, , 2006Cobos et al, , 2007. However, none of the opioid drugs (fentanyl, oxycodone, morphine, buprenorphine, tramadol, loperamide, naloxone, or naloxone methiodide) significantly inhibited [ (Fig.…”

Section: Modulation Of Peripheral M-opioid Analgesia By S 1 Receptorssupporting

confidence: 87%

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Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Sánchez-Fernández

Montilla-García

González‐Cano

et al. 2013

J Pharmacol Exp Ther

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We evaluated the effects of s 1 -receptor inhibition on m-opioidinduced mechanical antinociception and constipation. s 1 -Knockout mice exhibited marked mechanical antinociception in response to several m-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral m-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective A peripheral role for s 1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, s 1 -receptor inhibition did not alter fentanyl-or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, s 1 -receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral m-opioid analgesia without affecting opioidinduced constipation.

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Section: Modulation Of Peripheral M-opioid Analgesia By S 1 Receptorssupporting

confidence: 87%

“…Further dilutions were prepared with incubation buffer. The final maximal concentration of ethanol in the incubation medium was 0.1% (vol/vol), which did not affect [ 3 H](1)-pentazocine binding (Cobos et al, 2005(Cobos et al, , 2006.…”

Section: Methodsmentioning

confidence: 98%

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Sánchez-Fernández

Montilla-García

González‐Cano

et al. 2013

J Pharmacol Exp Ther

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“…The in vitro s 1 receptor assays were performed at pH 7.4 and 37°C in guinea pig brain membranes, where the K d of [ 3 H](1)-pentazocine is 2.3-2.9 nM (DeHaven-Hudkins et al, 1992;Cobos et al, 2005;Lever et al, 2006). Assays of Akunne et al (1997) were performed at pH 8.0 and 25°C, where the K d of [ 3 H](1)-pentazocine was reported as 4.7 nM.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

Lever

Miller

Fergason-Cantrell

et al. 2014

J Pharmacol Exp Ther

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Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (s 1 ) receptors. Selective s 1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity s 1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated s 1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for s 1 sites (K i 0.46 nM) and 3596-fold selectivity over s 2 sites (K i 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (K i .100 mM), and the DAT interaction was weak (K i 9.0 mM). In vivo, PD144418 bound to central and peripheral s 1 sites in mouse, with an ED 50 of 0.22 mmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 mmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 mmol/kg) attenuated cocaine-induced hyperactivity in a dosedependent manner in mice. There was good correlation (r 2 5 0.88) of hyperactivity reduction with increasing cerebral s 1 receptor occupancy. The behavioral ED 50 of 0.79 mmol/kg corresponded to 80% occupancy. Significant s 1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 mmol/kg dose of PD144418.

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“…There have been no other allosteric modulators found since the first report describing phenytoin as an allosteric modulator for the sigma-1 receptor (Cobos et al, 2005;DeHaven-Hudkins et al, 1993). We also compared the allosteric capability of SKF83959 with that of phenytoin.…”

Section: Discussionmentioning

confidence: 99%

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

et al. 2013

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-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 (D 1 receptor) agonist, has shown many D 1 receptor-independent effects, such as neuroprotection, blockade of Na 1 channel, and promotion of spontaneous glutamate release, which resemble the effects of the sigma-1 receptor activation. In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor. The results indicated that SKF83959 dramatically promoted the binding of 3 H(1)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues but produced no effect on 3 H-progesterone binding (a sigma-1 receptor antagonist). The saturation assay and the dissociation kinetics assay confirmed the allosteric effect. We further demonstrated that the SKF83959 analogs, such as SCH22390 [(R)-(1)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] and SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue. Moreover, all three tested chemicals elicited no significant effect on 3 H-1,3-di(2-tolyl)-guanidine ( 3 H-DTG) binding to the sigma-2 receptor. The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D 1 receptor-independent effect of the drug.

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Phenytoin differentially modulates the affinity of agonist and antagonist ligands for σ₁ receptors of guinea pig brain

Cited by 68 publications

References 17 publications

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

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Phenytoin differentially modulates the affinity of agonist and antagonist ligands for σ1 receptors of guinea pig brain

Cited by 68 publications

References 17 publications

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ1Receptors

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

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Phenytoin differentially modulates the affinity of agonist and antagonist ligands for σ₁ receptors of guinea pig brain

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors

Modulation of Peripheralμ-Opioid Analgesia byσ₁Receptors