Irreversible opiate agonists and antagonists: V. Hydrazone and acylhydrazone derivatives of naltrexone

Luke, Markham C.; Hahn, Elliot F.; Price, Maureen; Pasternak, Gavril W.

doi:10.1016/0024-3205(88)90215-9

Cited by 33 publications

(10 citation statements)

References 5 publications

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“…Drugs earlier defined pharmacologically as k 3 , including levorphanol (Moulin et al, 1988;Tive et al, 1992), nalorphine (Paul et al, 1991), and NalBzoH (naloxone benzoylhydrazone) (Luke et al, 1988;Gistrak et al, 1989;Paul et al, 1990) (Majumdar et al, 2011b). Equally important, their analgesic actions are greatly diminished in the exon 11 KO mouse, as is IBNtxA (Majumdar et al, 2011b).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

Grinnell

Majumdar

Narayan

et al. 2014

J Pharmacol Exp Ther

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IBNtxA (39-iodobenzoyl-6b-naltrexamide) is a potent analgesic in mice lacking many traditional opioid side effects. In mice, it displays no respiratory depression, does not produce physical dependence with chronic administration, and shows no crosstolerance to morphine. It has limited effects on gastrointestinal transit and shows no reward behavior. Biochemical studies indicate its actions are mediated through a set of m-opioid receptor clone MOR-1 splice variants associated with exon 11 that lack exon 1 and contain only six transmembrane domains. Like the mouse and human, rats express exon 11-associated splice variants that also contain only six transmembrane domains, raising the question of whether IBNtxA would have a similar pharmacologic profile in rats. When given systemically, IBNtxA is a potent analgesic in rats, with an ED 50 value of 0.89 mg/kg s.c., approximately 4-fold more potent than morphine. It shows no analgesic cross-tolerance in morphine-pelleted rats. IBNtxA displays no respiratory depression as measured by blood oxygen saturation. In contrast, oximetry shows that an equianalgesic dose of morphine lowers blood oxygen saturation values by 30%. IBNtxA binding is present in a number of brain regions, with the thalamus standing out with very high levels and the cerebellum with low levels. As in mice, IBNtxA is a potent analgesic in rats with a favorable pharmacologic profile and reduced side effects.

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Section: Discussionmentioning

confidence: 99%

Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

Grinnell

Majumdar

Narayan

et al. 2014

J Pharmacol Exp Ther

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“…Naloxone benzoylhydrazone (NalBzoH) was synthesized as previously reported (Luke et al, 1988). The OFQ/N peptides were synthesized by our Core Facility, purified by HPLC, and the structures verified by mass spectroscopy.…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

Identification of a high-affinity orphanin FQ/nociceptin(1-11) binding site in mouse brain

Mathis

Goldberg

Letchworth

et al. 1999

Synapse

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The presence of pairs of basic amino acids within the orphanin FQ/Nociceptin (OFQ/N) sequence has raised the possibility that truncated versions of the peptide might be physiologically important. OFQ/N(1-11) is pharmacologically active in mice, despite its poor affinity in binding assays (K(i) > 250 nM) for the OFQ/N receptor. Using an analog of OFQ/N(1-11), [(125)I][Tyr(10)]OFQ/N(1-11), we identified a high-affinity binding site (K(D) 234 pM; B(max) 43 fmol/mg protein) with a selectivity profile distinct from the OFQ/N receptor and all the traditional opioid receptors. This site had very high affinity for OFQ/N and its related peptides. The most striking differences between the new site and the OFQ/N receptor previously observed in brain were seen with traditional opioids. Dynorphin A analogs and alpha-neoendorphin competed with [(125)I][Tyr(10)]OFQ/N(1-11) binding in mouse brain with K(i) values below 10 nM, while naloxone benzoylhydrazone (K(i) 3.9 nM) labeled the [(125)I][Tyr(10)]OFQ/N(1-11) binding site as potently as many traditional opioid receptors. Several other opioids, including fentanyl, (-)cyclazocine, levallorphan, naltrindole, and diprenorphine, also displayed moderate affinities for this site. Finally, the [(125)I][Tyr(10)]OFQ/N(1-11) site had a unique regional distribution consistent with a distinct receptor. Thus, [(125)I][Tyr(10)]OFQ/N(1-11) labels a novel site in brain with a selectivity profile intermediate between that of either opioid or OFQ/N receptors.

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“…2), including b-funaltrexamine, naltrindole, and nor-binaltorphimine, that selectively inhibit mu, delta, and kappa 1 receptors, respectively (Portoghese et al, 1980(Portoghese et al, , 1987(Portoghese et al, , 1988; naloxonazine and naloxazone, which block a mu-receptor subtype (Pasternak et al, 1980a,b;Childers and Pasternak, 1982;; and naloxone benzoylhydrazone, a mu-antagonist/kappa 3 agonist (Hahn et al, 1985;Luke et al, 1988;Clark et al, 1989). Indeed, these have been extensively used to define receptor classes responsible for drug actions.…”

Section: A Alkaloidsmentioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

2013

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Irreversible opiate agonists and antagonists: V. Hydrazone and acylhydrazone derivatives of naltrexone

Cited by 33 publications

References 5 publications

Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

Pharmacologic Characterization in the Rat of a Potent Analgesic Lacking Respiratory Depression, IBNtxA

Identification of a high-affinity orphanin FQ/nociceptin(1-11) binding site in mouse brain

Mu Opioids and Their Receptors: Evolution of a Concept

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