Novel d-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral κ-opioid receptors,

Vanderah, Todd W.; Largent-Milnes, Tally M.; Lai, Josephine; Porreca, Frank; Houghten, Richard A.; Menzaghi, Frédérique; Wiśniewski, Kazimierz; Stalewski, Jacek; Sueiras-Diaz, Javier; Galyean, Robert; Schteingart, Claudio D.; Junien, J.L.; Trojnar, Jerzy; Rivière, Pierre

doi:10.1016/j.ejphar.2008.01.011

Cited by 88 publications

(106 citation statements)

References 26 publications

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“…Results of the present study are consistent with this characterization insofar as ICI204448, like ffir, produced dose-dependent antinociception in the assay of acid-stimulated stretching at doses that did not decrease ICSS in the absence of a noxious stimulus. These findings add to a growing body of evidence that stimulation of peripheral receptors may block reflexive manifestations of pain-related behavioral stimulation without producing more generalized signs of motor impairment (Barber et al, 1994;Vanderah et al, 2004Vanderah et al, , 2008. In this regard, peripherally selective agonists may be safer than centrally penetrating agonists that produce evidence of antinociception/analgesia only at doses that also produce untoward effects including sedation and (in humans) psychotomimesis.…”

Section: Discussionmentioning

confidence: 89%

“…These findings raise the possibility that agonists with greater peripheral selectivity than ffir, ICI204448, or asimadoline may display reduced propensity to act centrally and correspondingly greater efficacy to produce peripherally mediated blockade of pain-related behavioral depression. In support of this possibility, CR665 (H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-picolyl amide) has been described as a tetrapeptide agonist with very high peripheral selectivity in preclinical studies (Vanderah et al, 2008) and efficacy equivalent to oxycodone in one of two measures of mechanical visceral pain in humans (ArendtNielsen et al, 2009). CR665 was inactive on other measures of visceral and muscle pain, and it exacerbated responses to a cutaneous mechanical noxious stimulus, but further evaluation of agonists with high peripheral selectivity may be warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, ffir produced dose-dependent and norBNI-reversible antinociception in the assay of acid-stimulated stretching, and ffir was approximately 10-fold more potent in producing this antinociceptive effect than in decreasing ICSS in the absence of a noxious stimulus. Moreover, previous studies found that structurally related tetrapeptides also functioned as peripherally restricted agonists (Dooley et al, 1998;Vanderah et al, 2004Vanderah et al, , 2008. ICI204448 is a nonpeptidic small molecule that has also been described as a peripherally restricted -selective agonist (Shaw et al, 1989), and previous studies have reported dose-dependent and receptormediated antinociceptive effects in various assays of painstimulated behavior, including assays of acid-stimulated stretching in mice and rats (Barber et al, 1994;Keïta et al, 1995;Caram-Salas et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Negus¹,

O'Connell²,

Morrissey³

et al. 2011

J Pharmacol Exp Ther

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Opioid receptor agonists that do not readily cross the bloodbrain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central receptors. The present study used assays of painrelated stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted agonists [the, 2) a centrally penetrating agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal antiinflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted agonists had little effect, and salvinorin A exacerbated acidinduced depression of ICSS. These results suggest that peripherally restricted agonists may be safer than centrally penetrating agonists but less efficacious than NSAIDS or opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with agonists capable of greater peripheral selectivity are warranted.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Negus¹,

O'Connell²,

Morrissey³

et al. 2011

J Pharmacol Exp Ther

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“…A warm-water (50°C) tail flick assay was used to measure the sensitivity of the tail to a noxious thermal stimulus. Specifically, this assay measured a spinally and supraspinally mediated antinociceptive response, which provided an index of BBB permeation for morphine, a peripherally administered opioid agonist (Vanderah et al, 2008). Animals were gently held around the trunk, and the distal 2/3 of the tail was immersed in a 50°C constant temperature, circulating warm-water bath.…”

Section: Methodsmentioning

confidence: 99%

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

et al. 2013

Self Cite

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Effective pharmacologic treatment of pain with opioids requires that these drugs attain efficacious concentrations in the central nervous system (CNS). A primary determinant of CNS drug permeation is P-glycoprotein (P-gp), an endogenous blood-brain barrier (BBB) efflux transporter that is involved in brain-to-blood transport of opioid analgesics (i.e., morphine). Recently, the nuclear receptor constitutive androstane receptor (CAR) has been identified as a regulator of P-gp functional expression at the BBB. This is critical to pharmacotherapy of pain/inflammation, as patients are often administered acetaminophen (APAP), a CAR-activating ligand, in conjunction with an opioid. Our objective was to investigate, in vivo, the role of CAR in regulation of P-gp at the BBB. Following APAP treatment, P-gp protein expression was increased up to 1.4-1.6-fold in a concentration-dependent manner.Additionally, APAP increased P-gp transport of BODIPY-verapamil in freshly isolated rat brain capillaries. This APAP-induced increase in P-gp expression and activity was attenuated in the presence of CAR pathway inhibitor okadaic acid or transcriptional inhibitor actinomycin D, suggesting P-gp regulation is CAR-dependent. Furthermore, morphine brain accumulation was enhanced by P-gp inhibitors in APAP-treated animals, suggesting P-gp-mediated transport. A warm-water (50°C) tail-flick assay revealed a significant decrease in morphine analgesia in animals treated with morphine 3 or 6 hours after APAP treatment, as compared with animals treated concurrently. Taken together, our data imply that inclusion of APAP in a pain treatment regimen activates CAR at the BBB and increases P-gp functional expression, a clinically significant drugdrug interaction that modulates opioid analgesic efficacy.

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“…The tetrapeptide FE 200665 containing only (R)-configured amino acids represents an analgesically active drug, which activates selectively k receptors in the periphery [1][2][3] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Diastereoselective Synthesis of Cyclic Five‐Membered trans,trans‐Configured Nitrodiols by Double Henry Reaction of 1,4‐Dialdehydes

Fröhlich

Lehmkuhl

Fröhlich

et al. 2015

Archiv der Pharmazie

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Conformationally constrained perhydroquinoxalines 4 show high κ receptor affinity, selectivity over related receptors and full agonistic activity. Since the κ affinity can be correlated with the dihedral angle of the ethylenediamine pharmacophore (4a: 55°/71°), the dihedral angles of the postulated cyclopentane derivative 5a (73°/84°) and indane derivative 6a (77°/81°) were calculated. The first step of the synthesis represents a double Henry reaction of 1,4-dialdehydes 8 and 10 with nitromethane, leading predominantly to the trans,trans-configured nitrodiols 9 and 11. X-ray crystal structure analyses of 9 and 11 led to dihedral angles O2 N−C−C−OH of 73.4 and 88.3°, respectively, which reflect the calculated dihedral angles of the hypothesized final products 5a and 6a.

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Novel d-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral κ-opioid receptors,

Cited by 88 publications

References 26 publications

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

Diastereoselective Synthesis of Cyclic Five‐Membered trans,trans‐Configured Nitrodiols by Double Henry Reaction of 1,4‐Dialdehydes

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