- Trace amine-associated receptor 1 (TAAR1) is activated by amiodarone metabolites
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Amiodarone (Cordarone, Wyeth-Ayerst Pharmaceuticals) is a clinically available drug used to treat a wide variety of cardiac arrhythmias. We report here the synthesis and characterization of a panel of potential amiodarone metabolites that have significant structural similarity to thyroid hormone and its metabolites the iodothyronamines. Several of these amiodarone derivatives act as specific agonists of the G protein-coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR1). This result demonstrates a novel molecular target for amiodarone derivatives with potential clinical significance.
- Snead, Aaron N.,Miyakawa, Motonori,Tan, Edwin S.,Scanlan, Thomas S.
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supporting information; experimental part
p. 5920 - 5922
(2009/05/31)
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- Structure effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination
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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.
- Ha,Stieger,Grassi,Altorfer,Follath
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p. 807 - 814
(2007/10/03)
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