Potency Differences ford-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH<sub>2</sub>as an Antagonist of Peptide and Alkaloid μ-Agonists in an Antinociception Assay

Sterious, Steven; Walker, Ellen A.

doi:10.1124/jpet.102.042093

Cited by 16 publications

(30 citation statements)

References 24 publications

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“…Thus, in MOR-CHO cells, CTAP behaves not only as a -opioid receptor antagonist but also exhibits properties characteristic of inverse agonists as well. Notably, consistent with these findings, CTAP has been reported to possess a pharmacology that significantly differs from that of traditional opioid antagonists (Hawkins et al, 1989;Sterious and Walker, 2003). Inverse agonistic effects of CTAP on stimulated accumulation of cAMP is analogous to observations made for ICI174864 in ␦-opioid receptor expressing rat-1 fibroblasts (Merkouris et al, 1997) and human embryonic kidney cells stably expressing the ␦-opioid receptor (Chiu et al, 1996).…”

Section: Dual Effects Of Damgo and Ctap On Adenylyl Cyclase 259supporting

confidence: 70%

“…The other notable finding of the present work is that CTAP, previously considered to be a neutral -opioid receptor antagonist based on in vivo and in vitro observations using other systems (Bonner et al, 1997;Sterious and Walker, 2003), enhanced FSK-stimulated AC activity (Figs. 2-4).…”

Section: Dual Effects Of Damgo and Ctap On Adenylyl Cyclase 259supporting

confidence: 51%

“…The present study investigates inverse agonist properties of a commonly used -opioid receptor (MOR) antagonist, D-PheCys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP). Although previously characterized as a neutral antagonist in vivo (Bonner et al, 1997;Sterious and Walker, 2003) and in GH 3 cells ), the present study reveals that it manifests inverse agonism in Chinese hamster ovary (CHO) cells stably transfected with the -opioid receptor (MOR-CHO), underscoring the plasticity of inverse agonist responsiveness and its dependence on local cellular factors. Additionally, use of two bacterial toxins commonly used to assess receptor G protein coupling, pertussis toxin (PTX) and cholera toxin (CTX), provides further pharmacological evidence for -opioid receptor coupling to G s and augmented -opioid receptorcoupled signaling via the G ␤␥ subunit after chronic morphine.…”

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confidence: 89%

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Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Szücs¹,

Boda²,

Gintzler³

2004

J Pharmacol Exp Ther

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The -opioid receptor (MOR) couples to multiple G proteins, of which coupling to G s has long been debated. As expected, in opioid naive Chinese hamster ovary cells expressing recombinant MOR, the predominant action of [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) is inhibitory. However, inactivation of G i /G o proteins via pertussis toxin (PTX) unmasks its ability to facilitate forskolin activation of adenylyl cyclase (AC) activity. Tolerance develops to this effect of DAMGO, which can also be attenuated by cholera toxin (CTX). The latter suggests G s mediation. D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), previously considered to be a neutral MOR antagonist, also produces a facilitation of forskolin (FSK) activation of AC that is augmented by chronic morphine. Facilitative effects of CTAP in naive as well as its augmentation in tolerant membranes are both substantially reduced by CTX. This suggests that not only G s mediation but also G s␣ -linked signaling is critical to the chronic morphine-induced enhanced facilitative action of CTAP. Interestingly, the (augmented) CTAP facilitation of FSKstimulated AC activity that is observed in opioid tolerant (but not in naive) membranes is also sensitive to PTX. This can best be explained by postulating the involvement of G i -derived G ␤␥ , which would stimulate type 2 ACs, conditional on the presence of activated G s␣ . The emergence of a G ␤␥ dimension of AC stimulation by CTAP after chronic morphine could explain its ability to augment the stimulatory action of CTAP on AC. These results support putative MOR coupling to G s and underscore the multifaceted nature and plasticity of MOR G protein coupling.Traditionally, ligands acting on a G protein-coupled receptor (GPCR) are classified as either agonists, partial agonists, or antagonists. Recent findings, however, suggest that several compounds traditionally considered to be competitive (neutral) antagonists at GPCRs that are physiologically expressed at a low level can exhibit inverse agonist properties, i.e., have negative intrinsic activity (signaling efficacy) when these receptors and/or their cognate G proteins are present at higher levels of expression (Costa and

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Section: Dual Effects Of Damgo and Ctap On Adenylyl Cyclase 259supporting

confidence: 70%

Section: Dual Effects Of Damgo and Ctap On Adenylyl Cyclase 259supporting

confidence: 51%

mentioning

confidence: 89%

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Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Szücs¹,

Boda²,

Gintzler³

2004

J Pharmacol Exp Ther

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“…When tested in the opioid-dependent state, the classic opioid antagonists naloxone and naltrexone act as inverse agonists in vitro, whereas in opioid-naive cells, they do not perturb signaling to any significant extent (Wang et al, 1994(Wang et al, , 2001(Wang et al, , 2004. In contrast, the -opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) acts as a neutral antagonist in vitro, athough producing a less severe withdrawal than naloxone or naltrexone in opioid-dependent animals (Maldonado et al, 1992a;Wang et al, 1994;Bilsky et al, 1996;Cruz et al, 1996;Liu and Prather, 2001;Sterious and Walker, 2003).…”

mentioning

confidence: 99%

In Vivo Characterization of 6β-Naltrexol, an Opioid Ligand with Less Inverse Agonist Activity Compared with Naltrexone and Naloxone in Opioid-Dependent Mice

Raehal

Lowery²,

Bhamidipati³

et al. 2005

J Pharmacol Exp Ther

138

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The -opioid receptor displays basal signaling activity, which seems to be enhanced by exposure to opioid agonists. This study assesses the in vivo pharmacology of the putative "neutral" antagonist 6␤-naltrexol in comparison to other ligands with varying efficacy, such as naloxone, an inverse agonist in the opioid-dependent state. ICR mice were used to generate full antagonist dose-response curves for naloxone, naltrexone, nalbuphine, and 6␤-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6␤-Naltrexol was roughly equipotent to naloxone and between 4.5-and 10-fold less potent than naltrexone in blocking morphine-induced antinociception and locomotor activity, showing that 6␤-naltrexol enters the central nervous system. In contrast to naloxone and naltrexone, 6␤-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was ϳ77-and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic dependence model. 6␤-Naltrexol reduced the inverse agonist effects of naloxone in vitro and in vivo, as expected for a neutral antagonist. Therefore, the pharmacological effects of 6␤-naltrexol differ markedly from those of naloxone and naltrexone in the opioid-dependent state. A reduction of withdrawal effects associated with neutral -opioid receptor antagonists may offer advantages in treating opioid overdose and addiction.Basal signaling/constitutive activity of G-protein coupled receptors is now firmly established largely on the basis of in vitro results (Kenakin, 2003(Kenakin, , 2004a, with receptor ligands displaying a range of efficacies from full agonists to full inverse agonists. However, for receptor systems that display constitutive activity, many questions remain to be resolved. 1) Do the in vitro observations translate into changes that can be measured in vivo? 2) Are there clinical applications for inverse agonists versus neutral antagonists? 3) How is basal receptor activity regulated, and how does disease and/or chronic drug exposure alter levels of basal signaling and ligand efficacy? Studies on ␤-adrenergic receptors, for example, suggest that these issues may contribute to patient outcomes in diseases such as congestive heart failure and asthma (Maack et al., 2000;Callaerts-Vegh et al., 2004).We and others have established that the -and ␦-opioid receptors display basal signaling, which is altered by exposure to opioid agonists (Costa and

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“…For example, it can be calculated from Sterious and Walker (2003) that an icv dose of 3 nmol of the opioid antagonist naltrexone shifts the μ opioid analgesic dose-response curve in rats two-fold. Similarly, Lichtman and Martin (1997) allows an icv in vivo K d value to be calculated as 32 nmol for the CB 1 antagonist SR141716A on rat cannabinoid analgesic curves.…”

Section: Discussionmentioning

confidence: 99%

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

Hough

Nalwalk

Phillips³

et al. 2007

Neuropharmacology

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SummaryImprogan, a chemical congener of cimetidine, is a highly effective non-opioid analgesic when injected into the CNS. Despite extensive characterization, neither the improgan receptor, nor a pharmacological antagonist of improgan has been previously described. Presently, the specific binding of 3 H-cimetidine (3HCIM) in brain fractions was used to discover 4(5)-((4-iodobenzyl) thiomethyl)-1H-imidazole, which behaved in vivo as the first improgan antagonist. The synthesis and pharmacological properties of this drug (named CC12) are described herein. In rats, CC12 (50 -500 nmol, icv) produced dose-dependent inhibition of improgan (200 -400 nmol) antinociception on the tail flick and hot plate tests. When given alone to rats, CC12 had no effects on nociceptive latencies, or on other observable behavioral or motor functions. Maximal inhibitory effects of CC12 (500 nmol) were fully surmounted with a large icv dose of improgan (800 nmol), demonstrating competitive antagonism. In mice, CC12 (200-400 nmol, icv) behaved as a partial agonist, producing incomplete improgan antagonism, but also limited antinociception when given alone. Radioligand binding, receptor autoradiography, and electrophysiology experiments showed that CC12's antagonist properties are not explained by activity at 25 sites relevant to analgesia, including known receptors for cannabinoids, opioids or histamine. The use of CC12 as an improgan antagonist will facilitate the characterization of improgan analgesia. Furthermore, because CC12 was also found presently to inhibit opioid and cannabinoid antinociception, it is suggested that this drug modifies a biochemical mechanism shared by several classes of analgesics. Elucidation of this mechanism will enhance understanding of the biochemistry of pain relief.

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Potency Differences ford-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH₂as an Antagonist of Peptide and Alkaloid μ-Agonists in an Antinociception Assay

Cited by 16 publications

References 24 publications

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

In Vivo Characterization of 6β-Naltrexol, an Opioid Ligand with Less Inverse Agonist Activity Compared with Naltrexone and Naloxone in Opioid-Dependent Mice

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

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Potency Differences ford-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2as an Antagonist of Peptide and Alkaloid μ-Agonists in an Antinociception Assay

Cited by 16 publications

References 24 publications

Dual Effects of DAMGO [d-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor GsCoupling

Dual Effects of DAMGO [d-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor GsCoupling

In Vivo Characterization of 6β-Naltrexol, an Opioid Ligand with Less Inverse Agonist Activity Compared with Naltrexone and Naloxone in Opioid-Dependent Mice

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

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Product

Resources

About

Potency Differences ford-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH₂as an Antagonist of Peptide and Alkaloid μ-Agonists in an Antinociception Assay

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling