2-Carbomethoxy-3-(diarylmethoxy)-1 alpha H, 5 alpha H-tropane analogs: synthesis and inhibition of binding at the dopamine transporter and comparison with piperazines of the GBR series.

Article Details

Citation

Copy to clipboard

Meltzer PC, Liang AY, Madras BK

2-Carbomethoxy-3-(diarylmethoxy)-1 alpha H, 5 alpha H-tropane analogs: synthesis and inhibition of binding at the dopamine transporter and comparison with piperazines of the GBR series.

J Med Chem. 1996 Jan 19;39(2):371-9.

PubMed ID

8558504 [ View in PubMed

]

Abstract

We recently reported a new class of tropanes, based on benztropine, that bind uniquely, in the S-configuration, to the dopamine transporter. We have now extended this series to evaluate the effects of substituents on the nitrogen and the diarylmethoxy group. Herein we have described the synthesis and biological evaluation of a series of 2-carbomethoxy-3-(diaryl-methoxy)-1 alpha H, 5 alpha H-tropane (2-carbomethoxybenztropine) analogs. Examination of the binding data obtained for these compounds shows that while the 4,4'-difluoro compound is potent and selective for the dopamine transporter, introduction of larger groups such as 4,4'-dichloro, 4,4'- dibromo, 4,4'-diiodo, or 4,4'dimethyl on the 3-diphenylmethoxy moiety reduces this potency. However, although introduction of only one group (e.g., 4-chloro, 4-bromo, 4-iodo, or 4-methyl) leads to a similar reduction of binding affinity, these monosubstituted 2-carbomethoxybenztropines are significantly more potent than the related disubstituted compounds. Finally, from the data for the N-substituted 2-carbomethoxybenztropine analogs, it is evident that steric bulk can be tolerated at the nitrogen site. A comparison of structure-activity relationship data for the tropanes, GBR analogs, and these benztropines indicates that the 2-carbomethoxybenztropine analogs may be more like the GBR analogs in their mode of binding to the dopamine transporter than like the tropanes. This conclusion supports the notion that the binding site for (-)-cocaine [and the (1R)-tropanes] may differ from of the 2-carbomethoxybenztropine analogs.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Benzatropine	Sodium-dependent dopamine transporter	IC 50 (nM)	312	N/A	N/A	Details