American Chemical Society
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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

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journal contribution
posted on 1996-12-06, 00:00 authored by Craig E. Thomas, Patrick Bernardelli, S. Marc Bowen, Stephen F. Chaney, Dirk Friedrich, David A. Janowick, Bryan K. Jones, Frederick J. Keeley, John H. Kehne, Bert Ketteler, David F. Ohlweiler, Leo A. Paquette, David J. Robke, Thomas L. Fevig
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 ip.