HZ2, a Selective Kappa‐Opioid Agonist

Kögel, Babette; Christoph, Thomas; Friderichs, Elmar; Hennies, Hagen‐Heinrich; Matthiesen, T; Schneider, Johannes; Holzgrabe, Ulrike

doi:10.1111/j.1527-3458.1998.tb00041.x

Cited by 35 publications

(20 citation statements)

References 41 publications

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“…The affinity and potency of 3FLB for the opioid receptor were ϳ20-and ϳ30-fold, respectively, lower than that of U50,488H in this study. HZ2, the parent compound of 3FLB, was reported to be selective for the opioid receptor in rat brain membranes with K i 15 nM, and its affinity was 2-to approximately 4-fold lower than those of U50,488H and U69,593 (Kogel et al, 1998). Thus, 3FLB exhibited lower affinity than HZ2 for the opioid receptor.…”

Section: Discussionmentioning

confidence: 95%

“…It was demonstrated that HZ2 produced a strong antinociceptive effect in acetic acid abdominal constriction, hot plate, tail-flick, and tooth pulp stimulation tests (Kogel et al, 1998). HZ2 showed an unusually long duration of action in the mouse tail-flick test.…”

Section: Discussionmentioning

confidence: 99%

“…HZ2 showed an unusually long duration of action in the mouse tail-flick test. HZ2 caused other opioid receptorrelated effects, such as sedation and diuresis (Kogel et al, 1998). HZ2 also elicited emesis, which is not typical for opioid receptor agonists (Kogel et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…HZ2 exhibited high affinity for the opioid receptor in rat brain membranes (Siener et al, 2000). HZ2 also showed a strong and long-lasting antinociceptive effect in the mouse tail-flick test (Kogel et al, 1998). To the best of our EGTA, and 0.1 mM phenylmethylsulfonyl fluoride), passed through a 26 ϫ three-eighths-gauge needle 10 times and then centrifuged at 46,000g for 30 min.…”

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confidence: 99%

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Comparison of Pharmacological Activities of Three Distinct κ Ligands (Salvinorin A, TRK-820 and 3FLB) on κ Opioid Receptors in Vitro and Their Antipruritic and Antinociceptive Activities in Vivo

Wang¹,

Kang²,

Inan³

et al. 2004

J Pharmacol Exp Ther

178

155

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Salvinorin A, acrylamido]morphinan hydrochloride), and 3FLB (diethyl 2,4-di-[3-fluorophenyl]-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate) are structurally distinctly different from U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate], the prototypic selective agonist. Here, we investigated their in vitro pharmacological activities on receptors expressed in Chinese hamster ovary cells and in vivo antiscratch and antinociceptive activities in mice. All three compounds showed high selectivity for the opioid receptor (KOR) over the opioid receptor (MOR) and ␦ opioid receptor (DOR) and nociceptin or orphanin FQ receptors. In the guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding assay, all three were full agonists on the KOR. The rank order of affinity and potency for the KOR was TRK-820 Ͼ Ͼ U50,488H ϳ salvinorin A Ͼ Ͼ 3FLB. TRK-820 acted as a partial agonist on MOR and DOR, whereas salvinorin A and 3FLB showed no activities on these receptors. Salvinorin A, TRK-820, and 3FLB caused internalization of the human KOR in a dosedependent manner. Interestingly, although salvinorin A and U50,488H had similar potencies in stimulating [ 35 S]GTP␥S binding, salvinorin A was about 40-fold less potent than U50,488H in promoting internalization. Following 4-h incubation, all three compounds induced down-regulation of the human KOR, with salvinorin A causing a lower extent of down-regulation. Although TRK-820 was potent and efficacious against compound 48/80-induced scratching, salvinorin A showed low and inconsistent effects, and 3FLB was inactive. In addition, salvinorin A and 3FLB were not active in the acetic acid abdominal constriction test. The discrepancy between in vitro and in vivo results may be due to in vivo metabolism of salvinorin A and 3FLB and possibly to their effects on other pharmacological targets.At least three types of opioid receptors, , ␦, and , mediate pharmacological effects of opioid drugs and physiological actions of endogenous peptides (for review, see Chang, 1984;Mansour et al., 1988). Opioid receptors are coupled to G i /G o proteins to affect several different effectors, including inhibition of adenylyl cyclase, enhancement of K ϩ conductance, decrease in Ca 2ϩ conductance, and activation of p42/p44 mitogen-activated protein kinases (for review, see Law et al., 2000). In addition, opioid receptors are shown to act through Gz to inhibit adenylyl cyclase and G 16 to activate phospholipase C (Lai et al., 1995;Lee et al., 1998), and opioid receptors stimulate Na , ␦, and opioid receptors of several species have been cloned (for review, see Kieffer, 1995;Knapp et al., 1995). In addition, a receptor with high sequence similarity to the opioid receptors, termed the ORL1 receptor, was cloned and found to be coupled to G i /G o proteins (for review, see Kieffer, 1995;Knapp et al., 1995). Subsequently, the endogenous ligand for the ORL1 receptor was identified and named noThis work was supported by National I...

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Comparison of Pharmacological Activities of Three Distinct κ Ligands (Salvinorin A, TRK-820 and 3FLB) on κ Opioid Receptors in Vitro and Their Antipruritic and Antinociceptive Activities in Vivo

Wang¹,

Kang²,

Inan³

et al. 2004

J Pharmacol Exp Ther

178

155

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“…All compounds synthesized were subjected to radioligand binding assays using [4,5,6]. Since the affinities measured in different assays are not directly comparable, for sake of comparison HZ2, its oxalate salt, bremazocine and U-50,488 were additionally measured.…”

Section: 1]nonanonesmentioning

confidence: 99%

Stereochemistry and opioid receptor affinity of 2,4‐dipyridine‐3,7‐diazabicyclo[3.3.1]nonanones ‐ influence of the substituent in position N7

Cambareri¹,

Zlotos²,

Holzgrabe³

et al. 2002

Journal of Heterocyclic Chem

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The stereochemistry the 2,4-di-arene substituted 3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-dicarboxylate skeleton was found to be regulated by the kind of substituents attached to the arene rings as well as to the nitrogens N3 and N7. Conformational isomers, i.e., chair/chair, boat/chair and chair/boat, in addition to cis/trans configurational isomerism with respect to the arene rings were reported. Since the analgesic potency of the diazabicyclononanones, which is related to their affinity toward the κ-opioid receptor, is governed by the stereochemistry of the molecules, the influence of the substituents at nitrogen N7 was studied herein. The various differently N7 substituted diazabicyclononanones were found to crystallise in a highly symmetrical chair/chair conformation. However, beside HZ2 none of the compounds exhibits high affinity to the κ receptor. In contrast, some compounds with affinity to the µ receptor could be identified. In addition, the N7-(4-carboxybenzyl) substituted compound was found to have affinity to the δ receptor in the submicromolar range of concentration.

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Narcotic Analgesics

Aldrich

Vigil‐Cruz

2003

Burger's Medicinal Chemistry and Drug Discovery

147

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Narcotic analgesics such as morphine have been the mainstay for the treatment of severe pain, although these drugs are associated with serious adverse effects, most notably addiction liability and respiratory depression. Therefore there has been an intensive effort to find new therapeutic agents that retain the effectiveness of morphine, but do not have its undesired side effects. Compounds have been identified from a wide variety of chemical classes, from the rigid morphinan alkaloids to the flexible phenylpiperidines and the opioid peptides, which have affinity for opioid receptors. In recent years considerable effort has focused on identifying ligands, both agonists and antagonists, with affinity for delta (δ) and kappa (κ) opioid receptors as pharmacological tools and as potential therapeutic agents that would not have the side‐effect profile of morphine and other agonists that interact with mu (μ) opioid receptors. After the identification of the closely related opioid receptor‐like (ORL1) receptor and its endogenous ligand orphanin FQ/nociceptin, there has been considerable effort directed toward identifying agonists and antagonists for this receptor as well. This review discusses the structure‐activity relationships for each of the major classes of compounds that interact with the opioid receptors, along with ligands for the ORL1 receptors.

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HZ2, a Selective Kappa‐Opioid Agonist

Cited by 35 publications

References 41 publications

Comparison of Pharmacological Activities of Three Distinct κ Ligands (Salvinorin A, TRK-820 and 3FLB) on κ Opioid Receptors in Vitro and Their Antipruritic and Antinociceptive Activities in Vivo

Comparison of Pharmacological Activities of Three Distinct κ Ligands (Salvinorin A, TRK-820 and 3FLB) on κ Opioid Receptors in Vitro and Their Antipruritic and Antinociceptive Activities in Vivo

Stereochemistry and opioid receptor affinity of 2,4‐dipyridine‐3,7‐diazabicyclo[3.3.1]nonanones ‐ influence of the substituent in position N7

Narcotic Analgesics

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