- Synthesis and Structure-Activity Relationships of 5′-Aryl-14-alkoxypyridomorphinans: Identification of a μ Opioid Receptor Agonist/δOpioid Receptor Antagonist Ligand with Systemic Antinociceptive Activity and Diminished Opioid Side Effects
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We previously identified a pyridomorphinan (6, SRI-22138) possessing a 4-chlorophenyl substituent at the 5′-position on the pyridine and a 3-phenylpropoxy at the 14-position of the morphinan as a mixed μ opioid receptor (MOR) agonist and /κ opioid receptor (DOR/KOR) antagonist with potent antinociceptive activity and diminished tolerance and dependence in rodents. Structural variations at the 5′- and 14-positions of this molecule gave insights into the structure-activity relationships for binding and functional activity. Subtle structural changes exerted significant influence, particularly on the ability of the compounds to function as agonists at the MOR. In vivo evaluation identified compound 20 (SRI-39067) as a MOR agonist/DOR antagonist that produced systemically active potent antinociceptive activity in tail-flick assay in mice, with diminished tolerance, dependence/withdrawal, reward liability, and respiratory depression versus morphine. These results support the hypothesis that mixed MOR agonist/DOR antagonist ligands may emerge as novel opioid analgesics with reduced side effects.
- Vekariya, Rakesh H.,Lei, Wei,Ray, Abhisek,Saini, Surendra K.,Zhang, Sixue,Molnar, Gabriella,Barlow, Deborah,Karlage, Kelly L.,Bilsky, Edward J.,Houseknecht, Karen L.,Largent-Milnes, Tally M.,Streicher, John M.,Ananthan, Subramaniam
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- COMPOUNDS AND METHODS FOR INHIBITING PRODUCTION OF TRIMETHYLAMINE
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The invention provides a method of inhibiting the conversion of choline or carnitine to trimethylamine (TMA) and lowering TMAO in an individual comprising administering to the individual a composition comprising a compound set forth in FORMULA (I): The in
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Paragraph 0114; 0115; 0123; 0124
(2017/07/01)
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- CATALYST AND PROCESS FOR SYNTHESISING THE SAME
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The invention relates to a method for synthesising tethered ruthenium catalysts and novel tethered ruthenium catalysts obtainable by this methods. The method involves carrying out an "arene swapping" reaction avoiding the requirement to use complicated techniques making use of unreliable Birch reductions and unstable cyclodienyl intermediates.
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Page/Page column 66
(2014/05/24)
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