Abstract
A series of 1"-mono-, di-, and trifluorinated analogs of propranolol and related steric congeners was prepared, and their metabolism was examined with recombinant-expressed CYP1A2. The structural changes in this series of compounds, principally added fluorines and methyl groups in the 1"-position of theN-isopropyl group, provided compounds that varied in pKa by more than 5 log units, in log D by 3 log units, and in size of the added substituents.N-Dealkylation and aromatic hydroxylation (formation of the 4′- and 5′-regioisomers) were catalyzed by CYP1A2. Correlations of the metabolic kinetic parameters Km and catalytic efficiency (kcat/Km) with physicochemical properties pKa and log D showed that increased lipophilicity (higher log D values) was associated with increased affinity (lowerKm) and increased catalytic efficiency for CYP1A2. Comparison of log Km and logkcat/Km with pKa showed that the less basic analogs had higher affinities and increased catalytic efficiencies. The changes associated with pKa reflect increased lipid partitioning of substrate (increased log D) caused by an increase in the proportion of nonionized substrate. Increased steric bulk in theN-substituent alone did not decrease substrate affinity for CYP1A2 but did increase the amount of aromatic hydroxylation versusN-dealkylation. Removal of the hydroxyl group from the propanolamine side chain of propranolol resulted in a similar change in regioselectivity of metabolism.
Footnotes
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Partial support of this work was provided by National Research Service Award GM-07750 (Pharmacological Sciences Training Grant) and the Hope Barnes and Pfizer Fellowships.
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Partial support of this work was provided by National Research Service Award GM-07750 (Pharmacological Sciences Training Grant) and the Hope Barnes and Pfizer Fellowships.
- Abbreviations used are::
- P
- propranolol
- DIP
- desisopropylpropranolol
- OHP
- hydroxypropranolol
- MeIQ
- 2-amino-3,4-dimethylimidazo[4,5-f]quinoline
- SRS
- substrate recognition site
- FP
- fluoropropranolol
- DFP
- difluoropropranolol
- TFP
- trifluoropropranolol
- OHTFP
- hydroxytrifluoropropranolol
- HPLC
- high-pressure liquid chromatography
- iPrMe
- 1",1"-dimethylpropranolol
- tBuMe
- 1",1",1"-trimethylpropranolol
- TFE
- N-trifluoroethyldesisopropylpropranolol
- desOHP
- deshydoxypropranolol
- desOHTFP
- deshydroxytrifluoropropranolol
- Received May 8, 2001.
- Accepted July 17, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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