Pharmacological properties of TRK-820 on cloned μ-, δ- and κ-opioid receptors and nociceptin receptor

Seki, Takahiro; Awamura, Shinichiro; Kimura, C.; Ide, Soichiro; Sakano, Koichi; Minami, Masabumi; Nagase, Hiroshi; Satoh, Masamichi

doi:10.1016/s0014-2999(99)00369-6

Cited by 82 publications

(67 citation statements)

References 30 publications

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“…3 H]bremazocine, which binds to the κ 2 -opioid receptor subtype (26). Furthermore, TRK-820, as well as the κ 3 -opioid receptor subtype agonist naloxone benzoylhydrazone, antagonized the nociceptin-induced inhibition of cAMP accumulation in CHO cells expressing the nociceptin receptor, which is structurally similar to the κ 3 -opioid receptor subtype (27).…”

Section: Discussionmentioning

confidence: 99%

Modification of κ-Opioid Receptor Agonist-Induced Antinociception by Diabetes in the Mouse Brain and Spinal Cord

Ohsawa

Kamei

2005

J Pharmacol Sci

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Abstract. The supraspinal and spinal antinociceptive effects of several κ-opioid receptor agonists were examined in diabetic and non-diabetic mice using the tail-flick assay. The antinociception induced by intrathecal (i.t.), but not intracerebroventricular (i.c.v.), CI-977, a highly selective κ 1 -opioid receptor agonist, in diabetic mice was less than that in non-diabetic mice. The antinociceptive effects of ICI-199,441 and R-84760, high potency κ 1 -opioid receptor agonists, given i.c.v., but not i.t., were attenuated in diabetic mice compared to those in nondiabetic mice. On the other hand, the antinociceptive effects of the new κ-opioid receptor agonist TRK-820, which has high affinity for κ 2 -and / or κ 3 -opioid receptors, injected both i.c.v. and i.t. in diabetic mice were markedly less than those in non-diabetic mice. These results indicate that the antinociceptive effects of those κ-opioid receptor agonists in diabetic mice are altered in a region-specific manner in the central nervous system (CNS). The dysfunction of κ-opioid receptor subtypes in diabetic mice may underlie this CNS region-specific variation in the effects of these κ-opioid receptor agonists.

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Section: Discussionmentioning

confidence: 99%

Modification of κ-Opioid Receptor Agonist-Induced Antinociception by Diabetes in the Mouse Brain and Spinal Cord

Ohsawa

Kamei

2005

J Pharmacol Sci

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“…We found that naloxone at 1 mg/ kg blocked both TRK-820-and morphine-induced antinociceptive effects. When the pharmacological properties of TRK-820 were analyzed using Chinese hamster ovary cells expressing cloned rat k -, m-and d-opioid receptors and human nociceptin receptor, TRK-820 was shown to act as a full agonist for the k-opioid receptor, a partial agonist for the m -opioid receptor, and a low-affinity antagonist for the nociceptin receptor (18). We can not deny the possibility that TRK-820 is relatively resistant to nor-binaltorphimine in cynomolgus monkeys because of partial m-agonistic action.…”

Section: Discussionmentioning

confidence: 99%

TRK-820, a Selective κ-Opioid Agonist, Produces Potent Antinociception in Cynomolgus Monkeys

Endoh

Tajima

Izumimoto

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid k-receptor agonist with pharmacological properties different from those produced by k 1-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly (i.m.) produced a potent antinociceptive effect that was 295-and 495-fold more potent than morphine with the 50°C and 55°C hot-water tests, respectively, and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine in the 50°C hot-water test. The duration of antinociceptive effects of TRK-820 treatment (0.01 and 0.03 mg /kg, i.m.) lasted more than 6 h, which was much longer than those of U-50,488H. The antinociception produced by the higher dose (0.03 mg/ kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine (3.2 and 10 mg / kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone effectively inhibited the antinociception induced by the higher doses of U-50,488H (1.0 mg / kg, i.m.) and morphine (10 mg/ kg, i.m.), respectively. These results indicate that the antinociception induced by TRK-820 is less sensitive to nor-binaltorphimine and suggest that it is mediated by the stimulation of a subtype of k-opioid receptor different from the k1-opioid receptor in cynomolgus monkeys.Keywords: k-Opioid agonist, Antinociceptive effect, TRK-820, Cynomolgus monkey, k -Opioid receptor subtype Systematic efforts in searching for compounds which selectively stimulate k -opioid receptors resulted in the development of the compound TRK-820, (-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride. It has been demonstrated previously that TRK-820 possesses a highly selective k -opioid receptor agonistic activity in bioassays with isolated guinea pig ileum and mouse vas deferens preparations (1). TRK-820 is also a selective and centrally acting k-opioid agonist with antinociceptive and sedative activity in rodents (2). This is supported by the finding that the antinociception induced by TRK-820 is selectively inhibited by the pretreatment with the k -opioid receptor antagonist nor-binaltorphimine, but not by the m -opioid receptor antagonist naloxone and @-opioid receptor antagonist naltrindole. Unlike the other k-opioid agonist pentazocine, which blocks m-opioid receptors, TRK-820 has little or no m-opioid receptor antagonistic properties. In behavioral studies, TRK-820 does not produce any significant place aversion or place preference using an unbiased place preference conditioning procedure in mice (3), although other k-opioid receptor agonist...

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“…Several other arylacetamide compounds, including U69,593, ICI 204,448, and asimadoline, were subsequently found to be selective for the KOR (Szmuszkovicz, 1999). In addition, several nonarylacetamide compounds have been reported to be selective KOR agonists, including salvinorin A (Roth et al, 2002) and TRK-820 (Seki et al, 1999). Norbinaltorphimine (Nor-BNI) is the first selective antagonist (Portoghese et al, 1987).…”

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confidence: 99%

Ligands Regulate Cell Surface Level of the Human κ Opioid Receptor by Activation-Induced Down-Regulation and Pharmacological Chaperone-Mediated Enhancement: Differential Effects of Nonpeptide and Peptide Agonists

Chen¹,

Chen²,

Wang³

et al. 2006

J Pharmacol Exp Ther

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Two peptide agonists, eight nonpeptide agonists, and five nonpeptide antagonists were evaluated for their capacity to regulate FLAG (DYKDDDDK)-tagged human opioid receptors (hKORs) stably expressed in Chinese hamster ovary cells after incubation for 4 h with a ligand at a concentration ϳ1000-fold of its EC 50 (agonist) or K i (antagonist) value. Dynorphins A and B decreased the fully glycosylated mature form (55-kDa) of FLAG-hKOR by 70%, whereas nonpeptide full agonists [2-(3,4-dichlorophenyl 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820), ethylketocyclazocine, bremazocine, asimadoline, and (RS)- [3-[1-[[(3,4-dichlorophenyl)acetyl]-methylamino]-2-(1-pyrrolidinyl)ethyl]phenoxy] acetic acid hydrochloride (ICI 204,448) caused 10 -30% decreases. In contrast, pentazocine (partial agonist) and etorphine (full agonist) up-regulated by ϳ15 and 25%, respectively. The antagonists naloxone and norbinaltorphimine also significantly increased the 55-kDa receptor, whereas selective , ␦, and D 1 receptor antagonists had no effect. Naloxone up-regulated the receptor concentration-and time-dependently and enhanced the receptor maturation extent, without affecting its turnover. Treatment with brefeldin A (BFA), which disrupts Golgi, resulted in generation of a 51-kDa form that resided intracellularly. Naloxone up-regulated the new species, indicating that its action site is in the endoplasmic reticulum as a pharmacological chaperone. After treatment with BFA, all nonpeptide agonists up-regulated the 51-kDa form, whereas dynorphins A and B did not, indicating that nonpeptide agonists act as pharmacological chaperones, but peptide agonists do not. BFA treatment enhanced down-regulation of the cell surface receptor induced by nonpeptide agonists, but not that by peptide agonists, and unmasked etorphine-and pentazocine-mediated receptor downregulation. These results demonstrate that ligands have dual effects on receptor levels: enhancement by chaperone-like effects and agonist-promoted down-regulation, and the net effect reflects the algebraic sum of the two.The opioid receptor (KOR) is one of the three major types (, ␦, and ) of opioid receptors that mediate physiological and pharmacological effects of opioids in vivo. Stimulation of the KOR generates many effects, such as antinociception (especially for visceral chemical pain), dysphoria, water diuresis, hypothermia, modulation of immune responses, and alleviation of craving for cocaine in addicts (reviewed in LiuChen, 2004). The cDNA clones of KORs have been isolated and characterized from several species including human, mouse, rat, guinea pig, zebra fish, frog, and Caenorhabditis elegans.

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Pharmacological properties of TRK-820 on cloned μ-, δ- and κ-opioid receptors and nociceptin receptor

Cited by 82 publications

References 30 publications

Modification of κ-Opioid Receptor Agonist-Induced Antinociception by Diabetes in the Mouse Brain and Spinal Cord

Modification of κ-Opioid Receptor Agonist-Induced Antinociception by Diabetes in the Mouse Brain and Spinal Cord

TRK-820, a Selective κ-Opioid Agonist, Produces Potent Antinociception in Cynomolgus Monkeys

Ligands Regulate Cell Surface Level of the Human κ Opioid Receptor by Activation-Induced Down-Regulation and Pharmacological Chaperone-Mediated Enhancement: Differential Effects of Nonpeptide and Peptide Agonists

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