Cyclic nitrone free radical traps: isolation, identification, and synthesis of 3,3-dimethyl-3,4-dihydroisoquinolin-4-ol N-oxide, a metabolite with reduced side effects
| Autor: | Jones Bk, Thomas Ce, Leo A. Paquette, Keeley Fj, Dirk Friedrich, Fevig Tl, Patrick Bernardelli, Janowick Da, Chaney Sf, Kehne Jh, Bowen Sm, Ohlweiler Df, Robke Dj, Ketteler B |
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| Rok vydání: | 1996 |
| Předmět: |
Male
Antioxidant Magnetic Resonance Spectroscopy Stereochemistry Metabolite medicine.medical_treatment Motor Activity medicine.disease_cause Chemical synthesis Mass Spectrometry Nitrone Lipid peroxidation Rats Sprague-Dawley chemistry.chemical_compound Blood serum Cerebellum Drug Discovery medicine Moiety Animals Cells Cultured chemistry.chemical_classification Free Radical Scavengers Isoquinolines Rats chemistry Molecular Medicine Nitrogen Oxides Oxidative stress |
| Zdroj: | Journal of medicinal chemistry. 39(25) |
| ISSN: | 0022-2623 |
| Popis: | A C-4 hydroxylated metabolite (2, 3,3-dimethyl-3,4-dihydroisoquinolin-4-ol N-oxide) of the previously described cyclic nitrone free radical trap 1 (3,3-dimethyl-3,4-dihydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) was isolated, identified, and synthesized. The metabolite (2), though a less potent antioxidant than 1 in an in vitro lipid peroxidation assay, showed greatly reduced acute toxicity and sedative properties. Several analogs of 2 were prepared in attempts to improve on its weak antioxidant activity while retaining the desirable side effect profile. Effective structural changes included replacement of the gem-dimethyl moiety with spirocycloalkane groups and/or oxidation of the alcohols to the corresponding ketones. All of the analogs were more lipophilic (log k'(w)) and more active in the standard lipid peroxidation assay than 2. In addition, some of the compounds were able to protect cerebellar granule cells against oxidative damage (an in vitro model of oxidative brain injury) with IC50 values well below the value of the lead compound 1. The ketones, as predicted, were much more potent than 2 (and 1) in both of the above assays (up to ca. 200-fold). However, only compounds with a hydroxyl or an acetate group at C-4 displayed significantly reduced acute toxicity and sedative properties relative to those of 1. Importantly, the diminishment of toxicity and sedation were not the result of a lack of brain penetration as both 2 and the corresponding ketone (3,3-dimethyl-3,4-dihydro-3H-isoquinolin-4-one N-oxide) achieved equal or greater brain levels than those of 1 when administered to rats i.p. |
| Databáze: | OpenAIRE |
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