9 results on '"Harris, Louis S."'
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2. Fumaroylamino-4,5-epoxymorphinansand Related Opioidswith Irreversible μ Opioid Receptor Antagonist Effects.
- Author
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Moynihan, HumphreyA., Derrick, Ian., Broadbear, Jillian H., Greedy, Benjamin M., Aceto, MarioD., Harris, Louis S., Purington, Lauren C. S., Thomas, Mark P., Woods, James H., Traynor, John R., Husbands, Stephen M., and Lewis, John W.
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- 2012
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3. Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects.
- Author
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Moynihan HA, Derrick I, Broadbear JH, Greedy BM, Aceto MD, Harris LS, Purington LC, Thomas MP, Woods JH, Traynor JR, Husbands SM, and Lewis JW
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- Analgesics, Opioid chemical synthesis, Animals, Brain drug effects, Brain metabolism, Haplorhini, Mice, Molecular Structure, Morphine Derivatives chemical synthesis, Narcotic Antagonists chemical synthesis, Receptors, Opioid, mu metabolism, Structure-Activity Relationship, Swine, Analgesics, Opioid pharmacology, Morphine Derivatives pharmacology, Narcotic Antagonists pharmacology, Nociception drug effects, Pain Measurement drug effects, Receptors, Opioid, mu antagonists & inhibitors
- Abstract
We have previously shown that cinnamoyl derivatives of 14β-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible μ opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid β-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of β-FNA is clearly κ opioid receptor (KOR) mediated.
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- 2012
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4. Mixed kappa/mu opioid receptor agonists: the 6 beta-naltrexamines.
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Cami-Kobeci G, Neal AP, Bradbury FA, Purington LC, Aceto MD, Harris LS, Lewis JW, Traynor JR, and Husbands SM
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- Animals, CHO Cells, Cricetinae, Cricetulus, Naltrexone pharmacology, Rats, Spectrometry, Mass, Electrospray Ionization, Naltrexone analogs & derivatives, Receptors, Opioid, kappa agonists, Receptors, Opioid, mu agonists
- Abstract
Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6 beta-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, nonselective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist and therefore somewhat similar to the previously evaluated analogues 3-6, while 12b displayed predominant MOR agonist activity.
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- 2009
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5. Probes for narcotic receptor mediated phenomena. 34. Synthesis and structure-activity relationships of a potent mu-agonist delta-antagonist and an exceedingly potent antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series.
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Hiebel AC, Lee YS, Bilsky E, Giuvelis D, Deschamps JR, Parrish DA, Aceto MD, May EL, Harris LS, Coop A, Dersch CM, Partilla JS, Rothman RB, Cheng K, Jacobson AE, and Rice KC
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- Analgesics chemistry, Analgesics pharmacology, Animals, Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, CHO Cells, Cricetinae, Cricetulus, Crystallography, X-Ray, Haplorhini, Humans, Mice, Models, Molecular, Molecular Structure, Quantum Theory, Radioligand Assay, Receptors, Opioid, kappa antagonists & inhibitors, Stereoisomerism, Structure-Activity Relationship, Analgesics chemical synthesis, Bridged Bicyclo Compounds, Heterocyclic chemical synthesis, Receptors, Opioid, delta antagonists & inhibitors, Receptors, Opioid, mu agonists
- Abstract
Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9alpha-methyl, C9-methylene, C9-keto, and C9alpha- and C9beta-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S)-(+)-14), and (1R,5S,9R)-(-)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S,9R)-(+)-15) had subnanomolar affinity at mu-opioid receptors (Ki = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a mu-opioid agonist and a mu-, delta-, and kappa-antagonist in [35S]GTP-gamma-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(-)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9beta-hydroxy) was a mu-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (1R,5R,9S)-(-)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9beta-OH substituent in (1R,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the mu-opioid receptor.
- Published
- 2007
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6. Effect of a 6-cyano substituent in 14-oxygenated N-methylmorphinans on opioid receptor binding and antinociceptive potency.
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Spetea M, Greiner E, Aceto MD, Harris LS, Coop A, and Schmidhammer H
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- Analgesics chemistry, Analgesics pharmacology, Animals, Brain metabolism, In Vitro Techniques, Mice, Mice, Inbred ICR, Morphinans chemistry, Morphinans pharmacology, Nitriles chemistry, Nitriles pharmacology, Rats, Receptors, Opioid metabolism, Receptors, Opioid, delta drug effects, Receptors, Opioid, delta metabolism, Receptors, Opioid, kappa drug effects, Receptors, Opioid, kappa metabolism, Receptors, Opioid, mu drug effects, Receptors, Opioid, mu metabolism, Structure-Activity Relationship, Analgesics chemical synthesis, Morphinans chemical synthesis, Nitriles chemical synthesis, Receptors, Opioid drug effects
- Abstract
In a continued effort to find new substitution patterns in morphinans that would produce strong antinociception while inducing lesser side effects, 4,5-oxygen bridge-opened 6-cyano-substituted N-methylmorphinans (1-3) were synthesized. All compounds showed high affinities in the low nanomolar range to the mu opioid receptor and decreased interaction with delta and kappa receptors, thus being mu selective. When tested in vivo, the 6-cyanomorphinanas acted as potent antinociceptive agents which were either more active or equipotent to their 6-keto analogues 4-6.
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- 2005
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7. Synthesis and biological evaluation of 14-alkoxymorphinans. 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the mu opioid receptor antagonist cyprodime.
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Spetea M, Schüllner F, Moisa RC, Berzetei-Gurske IP, Schraml B, Dörfler C, Aceto MD, Harris LS, Coop A, and Schmidhammer H
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- Analgesics, Opioid chemistry, Analgesics, Opioid pharmacology, Animals, Binding, Competitive, CHO Cells, Cricetinae, In Vitro Techniques, Mice, Morphinans chemistry, Morphinans pharmacology, Radioligand Assay, Rats, Structure-Activity Relationship, Analgesics, Opioid chemical synthesis, Morphinans chemical synthesis, Receptors, Opioid, mu antagonists & inhibitors
- Abstract
The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at mu, delta, and kappa opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the mu opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase mu affinity in the case of benzyloxy, while a phenylpropoxy group reduces mu affinity. The delta and kappa affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the mu opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at delta and kappa receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [(35)S]GTPgammaS binding assay, all tested compounds were partial agonists at mu and delta receptors. Compounds 8 and 17 showed antagonism at kappa receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.
- Published
- 2004
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8. Synthesis and biological evaluation of 14-alkoxymorphinans. 20. 14-phenylpropoxymetopon: an extremely powerful analgesic.
- Author
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Schütz J, Spetea M, Koch M, Aceto MD, Harris LS, Coop A, and Schmidhammer H
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- Analgesics, Opioid chemistry, Animals, Etorphine analogs & derivatives, Etorphine pharmacology, Guinea Pigs, Male, Mice, Mice, Inbred ICR, Morphinans chemistry, Morphine pharmacology, Morpholines chemistry, Nociceptors drug effects, Nociceptors physiology, Pain Measurement drug effects, Radioligand Assay, Rats, Reaction Time drug effects, Reaction Time physiology, Receptors, Opioid metabolism, Structure-Activity Relationship, Analgesics, Opioid chemical synthesis, Analgesics, Opioid pharmacology, Morphinans chemical synthesis, Morphinans pharmacology, Morpholines chemical synthesis, Morpholines pharmacology
- Abstract
The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors mu, kappa, delta), with 14-phenylpropoxymetopon (PPOM; 7) displaying the highest affinity for all three opioid receptor types. The most striking finding of this study is that the derivatives from the novel series of N-methyl-14-phenylpropoxymorphinans acted as extremely powerful antinociceptives with potencies higher than that of 14-methoxymetopon (1) and even etorphine. 14-Phenylpropoxymetopon (PPOM; 7) showed considerably increased potency in the in vivo assays in mice (25-fold in the tail-flick assay, 10-fold in the hot-plate assay, and 2.5-fold in the paraphenylquinone writhing test) when compared to etorphine, while it was equipotent to dihydroetorphine in the hot-plate assay and the paraphenylquinone writhing test and ca. twice as potent in the tail-flick assay than this reference compound. The 3-O-alkyl ethers of PPOM, compounds 6 and 8, showed less potency in in vivo assays, but partly surpassed the potency of the 3-OH analogue 14-methoxymetopon (1).
- Published
- 2003
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9. Synthesis and biological evaluation of 14-alkoxymorphinans. 18. N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: extending the scope of common structure-activity relationships.
- Author
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Greiner E, Spetea M, Krassnig R, Schüllner F, Aceto M, Harris LS, Traynor JR, Woods JH, Coop A, and Schmidhammer H
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- Analgesics, Opioid chemistry, Analgesics, Opioid pharmacology, Animals, CHO Cells, Cricetinae, Ligands, Male, Mice, Mice, Inbred ICR, Morphinans chemistry, Morphinans pharmacology, Pain Measurement, Radioligand Assay, Rats, Receptors, Opioid, delta agonists, Receptors, Opioid, kappa agonists, Receptors, Opioid, mu agonists, Structure-Activity Relationship, Tumor Cells, Cultured, Analgesics, Opioid chemical synthesis, Morphinans chemical synthesis, Receptors, Opioid agonists
- Abstract
The synthesis, biological, and pharmacological evaluations of 14beta-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14beta-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (mu, kappa, delta), with the N-propyl derivative 19 displaying the highest affinity for the mu-receptor (K(i) = 0.09 nM).
- Published
- 2003
- Full Text
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