Synthesis and monoamine transporter binding properties of 2β-[3′-(substituted benzyl)isoxazol-5-yl]- and 2β-[3′-methyl-4′-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes Original Research Article

A series of 2β-[3′-(substituted benzyl)isoxazol-5-yl]- and 2β-[3′-methyl-4′-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes were prepared and evaluated for affinities at dopamine, serotonin, and norepinephrine transporters using competitive radioligand binding assays. The 2β-[3′-(substituted benzyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes (3a–h) showed high binding affinities for the dopamine transporter (DAT). The IC50 values ranged from 5.9 to 22 nM. On the other hand, the 2β-[3′-methyl-4′-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes (4a–h), with IC50 values ranging from 65 to 173 nM, were approximately 3- to 25-fold less potent than the corresponding 2β-[3′-(substituted benzyl)isoxazol]tropanes. All tested compounds were selective for the DAT relative to the norepinephrine transporter (NET) and serotonin transporter (5-HTT). 3β-(4-Methylphenyl)-2β-[3′-(4-fluorobenzyl)isoxazol-5-yl]tropane (3b) with IC50 of 5.9 nM at the DAT and Kis of 454 and 113 nM at the NET and 5-HTT, respectively, was the most potent and DAT-selective analog. Molecular modeling studies suggested that the rigid conformation of the isoxazole side chain in 4a–h might play an important role on their low DAT binding affinities.