Structure–effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination

1432-1041

Key words Amiodarone analogues ; 5′-T4 deiodinase ; Deiodination

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Abstract Objectives: Amiodarone (AMI) has proven to be a potent anti-arrhythmic compound. Due to the structural similarity between AMI and thyroid hormone, it is possible that the drug could inhibit the activity of the 5′-thyroxine-deiodinase. Methods: AMI analogues resulting from (1) dealkylation, (2) deiodination and (3) deamination were synthesised and used as inhibitors in an in vitro biotransformation reaction of thyroxine (T4) to 3,3′,5′-triiodothyronine (T3). Using high-performance liquid chromatography and ultraviolet detection for quantifying T3, it was found that the 5′-T4 deiodinase type I was involved in the reaction. On separate occasions, AMI or an AMI analogue was added to the reaction as an inhibitor. Results: All studied AMI analogues inhibited 5′-T4 deiodination competitively (K i value range 25–360 μM). In the concentration range of 1–1000 μM, AMI and its N-desethylated, deiodinated analogues inhibited 5′-T4 deiodination very weakly. AMI analogues with a hydroxyl group at the 4-position were strong inhibitors. Moreover, diiodo-AMI analogues inhibited 5′-T4 deiodination more strongly than their corresponding monoiodo- or deiodinated derivatives. Conclusion: It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.

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