Structure-Activity Relationship Studies on a Novel Series of (S)-2-Substituted 3
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- 作者：Mu-Fa Zou ; Jianjing Cao ; Theresa Kopajtic ; Rajeev I. Desai ; Jonathan L. Katz ; Amy Hauck Newman
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：October 19, 2006
- 年：2006
- 卷：49
- 期：21
- 页码：6391 - 6399
- 全文大小：123K
- 年卷期：v.49,no.21(October 19, 2006)
- ISSN：1520-4804
文摘
In general, 3
-(diphenylmethoxy)tropane (benztropine)-based dopamine uptake inhibitors do not demonstratecocaine-like pharmacological activity in models of psychostimulant abuse and have been proposed as potentialmedications for the treatment of cocaine addiction. However, several (S)-2-carboalkoxy-substituted-3-[bis(4-fluorophenyl)methoxy]tropane analogues were discovered to stimulate locomotor activity and substitutein subjects trained to discriminate cocaine, suggesting a role of the 2-position substituent in mediating thesecocaine-like actions. Herein, we describe the synthesis of a series of novel N- and 2-substituted-3-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues. Most of these analogues demonstrated high affinitybinding to the dopamine transporter (DAT; Ki = 1.8-40 nM), and selectivity over the other monoaminetransporters and muscarinic M1 receptors. When the (S)-2-carboalkoxy substituent was replaced with (S)-2-ethenyl, the resulting analogue 11 demonstrated the highest DAT binding affinity in the series (Ki = 1.81nM) with DAT selectivity over serotonin transporters (SERT; 989-fold), norepinephrine transporters (NET;261-fold) and muscarinic receptors (90-fold). When the 4'-F groups of compounds 5 (Ki = 2.94 nM) and8 (Ki = 6.87 nM) were replaced with 4'-Cl in the (S)-2-carboalkoxy series, DAT binding affinities wereslightly reduced (Ki = 12.6 and 14.6 nM for 6 and 7, respectively), yet inhibition of dopamine uptakepotency remained comparably high (IC50 range = 1.5-2.5 nM). Interestingly, the 4'-Cl analogue (±)-6substituted less in rats trained to discriminate cocaine than the 4'-F analogue (±)-5. These studies demonstratethat manipulation of the 2-, N-, and 3-position substituents in the 3-(diphenylmethoxy)tropane class ofdopamine uptake inhibitors can result in ligands with high affinity and selectivity for the DAT, and distinctivein vivo pharmacological profiles that cannot be predicted by their effects in vitro.
-(diphenylmethoxy)tropane (benztropine)-based dopamine uptake inhibitors do not demonstratecocaine-like pharmacological activity in models of psychostimulant abuse and have been proposed as potentialmedications for the treatment of cocaine addiction. However, several (S)-2-carboalkoxy-substituted-3-[bis(4-fluorophenyl)methoxy]tropane analogues were discovered to stimulate locomotor activity and substitutein subjects trained to discriminate cocaine, suggesting a role of the 2-position substituent in mediating thesecocaine-like actions. Herein, we describe the synthesis of a series of novel N- and 2-substituted-3-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues. Most of these analogues demonstrated high affinitybinding to the dopamine transporter (DAT; Ki = 1.8-40 nM), and selectivity over the other monoaminetransporters and muscarinic M1 receptors. When the (S)-2-carboalkoxy substituent was replaced with (S)-2-ethenyl, the resulting analogue 11 demonstrated the highest DAT binding affinity in the series (Ki = 1.81nM) with DAT selectivity over serotonin transporters (SERT; 989-fold), norepinephrine transporters (NET;261-fold) and muscarinic receptors (90-fold). When the 4'-F groups of compounds 5 (Ki = 2.94 nM) and8 (Ki = 6.87 nM) were replaced with 4'-Cl in the (S)-2-carboalkoxy series, DAT binding affinities wereslightly reduced (Ki = 12.6 and 14.6 nM for 6 and 7, respectively), yet inhibition of dopamine uptakepotency remained comparably high (IC50 range = 1.5-2.5 nM). Interestingly, the 4'-Cl analogue (±)-6substituted less in rats trained to discriminate cocaine than the 4'-F analogue (±)-5. These studies demonstratethat manipulation of the 2-, N-, and 3-position substituents in the 3-(diphenylmethoxy)tropane class ofdopamine uptake inhibitors can result in ligands with high affinity and selectivity for the DAT, and distinctivein vivo pharmacological profiles that cannot be predicted by their effects in vitro.