Evaluation of a Neurokinin1 antagonist, CP-99,994, in comparison to ibuprofen and placebo in the oral surgery model.

Dionne, Raymond A.; Max, Mitchell B.; Parada, Suzan; Gordon, Sharon M.; MacLcan, D.B.

doi:10.1038/sj.clpt.1996.365

Cited by 15 publications

(8 citation statements)

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“…However, low doses of U-50,488H and U-69,593 themselves induced aversive effects as measured by conditioned place preference procedures (Shippenberg and Herz 1988;Suzuki et al 1992). In humans, these κ-opioid receptor agonists cause dysphoria and psychotomimetic syndrome (Peters and Gaylor 1989;Dionne et al 1991), while TRK-820 did not cause psychotomimetic effects (Endoh et al 2000). Previous study demonstrated that TRK-820 did not engender place preference or place aversion (Nagase et al 1998).…”

Section: Discussionmentioning

confidence: 91%

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

et al. 2002

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TRK-820 did not engender cocaine-like responding in rats trained to discriminate between 10 mg/kg cocaine and saline. In combination tests, low doses of TRK-820, which did not affect the response rate, significantly attenuated the discriminative stimulus effects of cocaine, and these effects of TRK-820 were reversed by a kappa-opioid receptor antagonist, nor-BNI. In the conditioned place preference procedure, low doses of TRK-820, which did not affect the response rate in the drug discrimination, did not produce either place preference or place aversion, whereas, higher dose (80 microg/kg) of TRK-820 slightly but significantly induced a place aversion. Under these conditions, the cocaine-induced place preference was completely attenuated by low doses of TRK-820. These results may prompt further investigation of the effectiveness of the new kappa-opioid receptor agonist TRK-820 as a novel pharmacotherapeutic compound for the treatment of cocaine addiction.

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Section: Discussionmentioning

confidence: 91%

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

et al. 2002

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“…Single intramuscular injections of TRK-820 up to 30 mg are well tolerated by healthy volunteers, whereas a dose of 40 mg TRK-820 produces moderate behavioral/ psychological side effects, but not psychotomimetic activity (Toray Industries, Inc., unpublished data). Thus, TRK-820 was again shown to be different from other k -opioid receptor agonists, such as the arylacetamide spiradoline, which cause dysphoria and psychotomimetic reactions (5,6).…”

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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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“…[10]. However, a recent publication describes two placebocontrolled studies of the same compound in dental pain following oral surgery [11]. The study compared CP-99,994 (0.75 mg/kg iv.…”

Section: Cp-99994mentioning

confidence: 99%

Neurokinin receptor antagonists

Elliott

Seward

1997

Expert Opinion on Therapeutic Patents

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The competitive area of neurokinin (NK) receptor antagonists has recently seen the publication of early clinical results which provide strong support for their use in the treatment of pain, emesis and asthma. Preclinical models support their use in a number of additional disorders including anxiety, arthritis, migraine, cancer and schizophrenia. New indications, such as glaucoma and ocular hypotension, neuronal injury and stroke, cardiac disorders and topical applications have recently been claimed. Published patent applications from most of the major pharmaceutical companies claim a wide variety of structural classes as antagonists at all three neurokinin receptors. This review discusses the significance of new clinical data for ongoing drug discovery efforts, and patent claims for new indications and new structural classes for the period since the last review in early 1996.

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Evaluation of a Neurokinin1 antagonist, CP-99,994, in comparison to ibuprofen and placebo in the oral surgery model.

Abstract: Clinical Pharmacology & Therapeutics (1996) 59, 216–216; doi:

Cited by 15 publications

References 0 publications

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

Effects of a newly synthesized κ-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats

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

Neurokinin receptor antagonists

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