Inhibition of Cytochrome P450 2D6: Structure-Activity Studies Using a Series of Quinidine and Quinine Analogues
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- 作者：J. Matthew Hutzler ; Gregory S. Walker ; and Larry C. Wienkers
- 刊名：Chemical Research in Toxicology
- 出版年：2003
- 出版时间：April 2003
- 年：2003
- 卷：16
- 期：4
- 页码：450 - 459
- 全文大小：180K
- 年卷期：v.16,no.4(April 2003)
- ISSN：1520-5010
文摘
Several pharmacophore models have suggested that substrates and inhibitors of cytochromeP450 2D6 (P450 2D6) possess a nitrogen with a positive charge that participates in a charge-pair interaction with the aspartate 301 residue. In an effort to investigate this paradigm forP450 2D6 binding, an analogue series of the stereoisomers quinidine and quinine weresynthesized and screened for binding affinity as measured by inhibition. Results revealed thatbulky substituents added to the quinuclidine nitrogen (quaternary salts) did not affect theinhibitory potency of quinidine (IC50 = 0.02 
M), suggesting minimal contribution to bindingaffinity of this inhibitor by the purported ionic-binding interaction. Meanwhile, substantialdecreases in inhibitory potency were observed for the N-methyl, N-ethyl, and N-benzylquininium salts, suggesting that the quaternary nitrogen of this antipode interacts with adistinct region of the P450 2D6 active site as compared to the corresponding nitrogen ofquinidine. Interestingly, esterification of quinidine resulted in a substantial loss of inhibitorypotency, likely due to disruption of a hydrogen-bonding interaction of the hydroxyl group. Thissuggests that hydrogen bonding contributes more to the tight binding of quinidine than doesthe charge-pair interaction of the positively charged nitrogen. Moreover, benzoyl esterformation of quinine caused the binding orientation to switch from type II to type I, withconcomitant restoration of P450 2D6 inhibitory potency. Thus, it appears that both hydrogenbonding and the ionic interaction of the basic nitrogen of quinine contribute to inhibitorypotency, while the hydroxyl group also apparently contributes to directing type II binding.Overall, results suggest that when analyzing a series of compounds that include stereoisomersfor development of predictive pharmacophore/protein models describing P450 2D6 binding, itmay be inappropriate to assume that the ionic interaction of the basic nitrogen with aspartate301 represents the primary binding interaction.
M), suggesting minimal contribution to bindingaffinity of this inhibitor by the purported ionic-binding interaction. Meanwhile, substantialdecreases in inhibitory potency were observed for the N-methyl, N-ethyl, and N-benzylquininium salts, suggesting that the quaternary nitrogen of this antipode interacts with adistinct region of the P450 2D6 active site as compared to the corresponding nitrogen ofquinidine. Interestingly, esterification of quinidine resulted in a substantial loss of inhibitorypotency, likely due to disruption of a hydrogen-bonding interaction of the hydroxyl group. Thissuggests that hydrogen bonding contributes more to the tight binding of quinidine than doesthe charge-pair interaction of the positively charged nitrogen. Moreover, benzoyl esterformation of quinine caused the binding orientation to switch from type II to type I, withconcomitant restoration of P450 2D6 inhibitory potency. Thus, it appears that both hydrogenbonding and the ionic interaction of the basic nitrogen of quinine contribute to inhibitorypotency, while the hydroxyl group also apparently contributes to directing type II binding.Overall, results suggest that when analyzing a series of compounds that include stereoisomersfor development of predictive pharmacophore/protein models describing P450 2D6 binding, itmay be inappropriate to assume that the ionic interaction of the basic nitrogen with aspartate301 represents the primary binding interaction.