Structure-Activity Relationship Comparison of (S)-2β-Substituted 3α-(Bis4-fluorophenylmethyoxy)tropanes and (R)-2β-Substituted 3β-(3,4-Dichlorophenyl)tropanes at the Dopamine Transporter

摘要

Extensive structure-activity relationship at the dopamine transporter (DAT) have been developed around two classes of tropane-based ligands. Opposing stereoselectivity and divergent structural requirements for optimal DAT binding suggest that these tropane-based DAT inhibitors may not access identical binding domains. To further investigate this hypothesis, a series of (S)-2β-carboalkoxy-3α-(bis4-fluorophenylmethoxy)tropanes (11a-f, 13-16) and their identically (R)-2β-substituted 3β-(3,4-dichlorophenyl)tropanes (3, 5a-d) were prepared and evaluated for binding at the DAT and for inhibition of ~3H dopamine uptake in rat brain. These studies showed that most of the identically 2-carboalkoxy-substituted analogues, within the two classes of compounds, bind with high affinity to DAT (K_i = 5.5-100 nM), albeit with opposite stereochemistry. However, the larger azido- (15) and isothiocyanato- (16) (S)-2β-carbophenylethoxy-3α-(bis4-fluorophenylmethoxy)tropanes demonstrated a significant decrease in DAT binding potency (IC_(50) = 210 and 537 nM, respectively), suggesting that the DAT does not tolerate 2-position steric bulk in the benztropine class, as it does with the 2-substituted 3-aryltropanes. In addition, binding affinities at the serotonin transporter, norepinephrine transporter, and muscarinic receptors were evaluated and compared for compounds 2, 3, 11a-e, and 13. Together, the binding profiles across these systems demonstrated significant differences between these two classes of tropane-based ligands, which may be exploited toward the discovery of a cocaine-abuse pharmacotherapeutic.