Discovery of an Opioid κ Receptor Selective Pure Antagonist from a Library of N-Substituted 4β-Methyl-5-(3-hydroxyphenyl)morphans

Thomas, James B.; Atkinson, Robert N.; Namdev, Nivedita; Rothman, RB; Gigstad, Kenneth M.; Fix, Scott; Mascarella, S. Wayne; Burgess, Jason P.; Vinson, N. Ariane; Xu, Heng; Dersch, CM; Cantrell, BE; Zimmerman, Dennis M.; Carroll, F. Ivy

doi:10.1021/jm020084h

Cited by 25 publications

(39 citation statements)

References 20 publications

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“…From a library of phenylmorphan scaffold, 7-[3-(1-piperidinyl)propanamido] morphan derivative (100) was identified as a potent and selective k opioid receptor antagonist. 176 The structure of this compound is similar to that of previously reported JDTic …”

Section: K-selective Agonists and Antagonistssupporting

confidence: 82%

Recent advances in selective opioid receptor agonists and antagonists

Eguchi

2003

Medicinal Research Reviews

145

112

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Opioid analgesics provide outstanding benefits for relief of severe pain. The mechanisms of the analgesia accompanied with some side effects have been investigated by many scientists to shed light on the complex biological processes at the molecular level. New opioid drugs and therapies with more desirable properties can be developed on the bases of accurate insight of the opioid ligand-receptor interaction and clear knowledge of the pharmacological behavior of opioid receptors and the associated proteins. Toward this goal, recent advances in selective opioid receptor agonists and antagonists including opioid ligand-receptor interactions are summarized in this review article.

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Section: K-selective Agonists and Antagonistssupporting

confidence: 82%

Recent advances in selective opioid receptor agonists and antagonists

Eguchi

2003

Medicinal Research Reviews

145

112

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“…Moreover, 16 is also more potent at κ receptors (approximately 16-fold, K e = 220 nM vs K e = 3600 nM) and δ receptors (2-fold, K e = 950 nM vs K e = 1770 nM). A change in the C2 stereochemistry in 16 (17) decreased activity 7-fold at μ receptors (K e = 1500 nM vs K e = 210 nM) and 2-fold at δ receptors (K e = 1700 nM vs K e = 950 nM) compared to 15. This change also decreased activity 9-fold at κ receptors (K e = 1900 nM vs K e = 220 nM).…”

Section: Resultsmentioning

confidence: 97%

Flavonoids as Opioid Receptor Ligands: Identification and Preliminary Structure−Activity Relationships

et al. 2007

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Flavonoids have been recognized as the active ingredients of many medicinal plant extracts due to interactions with proteins via phenolic groups and low toxicity. Here, we report the investigation of the flavonoid core as a potential new scaffold for the development of opioid receptor ligands. Biological results suggest that stereochemistry of the C2 and C3 positions is important for antagonist activity and selectivity. Our results also suggest that the actions of Hypericum perforatum may be mediated in part by opioid receptors.At present, effective pharmacotherapies have yet to be developed for cocaine and methamphetamine dependence. A large body of evidence in animal models indicates that κ receptors (and their endogenous opioid peptide ligands, e.g., the dynorphins) modulate the effects of these CNS stimulants. 1,2 The κ receptor/dynorphin system is thought to be part of the brain's counter-regulatory response to enhanced dopaminergic activity, which is thought to be a major initial event underlying drug-induced reinforcement and abuse potential. In particular, κ antagonists attenuate the reinstatement of extinguished drug-taking behavior (a model of relapse). 3Among the first nonpeptide κ antagonists identified were those derived from the nonselective antagonist naltrexone (1) such as nor-BNI (nor-binaltorphimine, 2a) and GNTI (5′-guanidinonaltrindole, 2b) (Chart 1). 4,5 While 2a has been extensively used to study κ opioid receptors, its pharmacological properties are not optimal, and it exhibits a much longer than expected half-life in vivo. 6 Further study 7-11 of its structure-activity relationships identified 2b as a κ antagonist. 12,13 Compound 2b has increased potency in vivo compared to 2a, but unfortunately also has a slow onset of action and a long half-life in vivo. 14 Recently, Thomas et al. identified several novel κ opioid receptor antagonists from several classes of opioids. 15-18 κ-Selective antagonists were identified from the 4-phenylpiperidine and the 5-phenylmorphan classes of opioids. In particular, JDTic ((3R)-7-hydroxy-N-(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-pi-peridinyl]methyl-2-methylpropyl-1,2,3,4-tetrahydro-3-isoquinolin-ecarboxamide, 3) was shown to be a more potent κ antagonist than 2a. 16 Biological studies have shown that 3 blocks κ-agonist-induced antinociception in mice and squirrel monkey and antagonizes κ-agonist-induced diuresis in rats. 19 A more recent study illustrated that 3 is effective in decreasing withdrawal signs in rodents, indicating 3 may find some application in the treatment of opiate abuse. 20 Furthemore, 3 significantly reduced footshock-induced reinstatement of cocaine responding in rats and decreased immobility and increased swimming time in the forced swim stress test similar to the antidepressant * To whom correspondence should be addressed. Tel: (319) Additional screening showed that 4 had significant δ opioid receptor affinity (K i = 36 nM) in vitro. 36 However, it was not known whether 4 was an agonist or an antagonist at δ opio...

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“…Such an interaction is consistent with our studies with κ selective 5-(3-hydroxyphenyl)morphans (4a, 27, and 28) where we found that the relative placement of the bridging ring and 4β-methyl group significantly impacted potency and selectivity for the κ receptor. 19,20 Another important aspect of the present study is that it adds additional support to the role of the trans-3,4-dimethyl structure or substructure that is essential for the antagonist activity of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) series, Figure 4. The 8a-methyl and the 5-position methylene of the bridging ring fulfill this role in the isoquinoline compounds 6a-g. Information as to the function of this and similar groups can be gleaned from the available literature.…”

Section: Discussionmentioning

confidence: 74%

N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists

et al. 2005

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N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3, 4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has the lower potential energy relative to the axial conformation. Evaluation of compounds 6a-g in the [ 35 S]GTP-γ-S in vitro functional assay showed that they were opioid receptor pure antagonists. octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a K e of 0.27 nM at the κ opioid receptor with 154-and 46-fold selectively relative to the μ and δ receptors, respectively, possessed the best combination of κ potency and selectivity.The opioid receptor system has been extensively studied, and thousands of compounds have been synthesized and evaluated by in vitro binding and functional assays as well as animal models. 1 An integral part of the effort to characterize the opioid receptor system has been the discovery of potent, pure antagonists. Naloxone (1a) and naltrexone (1b), both competitive antagonists at μ, δ, and κ opioid receptors, 1 have been extensively used as pharmacological tools to identify and characterize opioid systems. Additionally, naloxone (1a) is approved for treating heroin overdose and to reverse respiratory depression caused by morphine. 2 Naltrexone (1b) is used to treat heroin and alcohol abuse.Pioneering structure activity relationship (SAR) studies by Portoghese et al. based on the lead compound 1b lead to the discovery of the δ opioid receptor selective antagonist naltrindole (NTI, 2a) and the κ opioid receptor antagonists, norbinaltorphimine (3, norBNI) and guanidinenaltrindole (GNTI, 2b). [3][4][5][6]piperidines (4) are another interesting class of opioid receptor pure antagonist. Unlike other antagonists, including the oxymorphone class, antagonist activity was not NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dependent on the structure of the N-substituent. 1 All reported N-substituted analogues, including the N-methyl analogue 4a were antagonists. 1,7-12 A few of the more interesting analogues include alvimopan (4b), 13-15 which has reached the NDA stage for GI motility disorder, (3R,4R)-1-[(S)-3-hydroxy-3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine (LY255,582 (4c)), 16,17 which was developed to treat obesity and (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl] methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline...

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Discovery of an Opioid κ Receptor Selective Pure Antagonist from a Library of N-Substituted 4β-Methyl-5-(3-hydroxyphenyl)morphans

Cited by 25 publications

References 20 publications

Recent advances in selective opioid receptor agonists and antagonists

Recent advances in selective opioid receptor agonists and antagonists

Flavonoids as Opioid Receptor Ligands: Identification and Preliminary Structure−Activity Relationships

N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists

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