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

Abstract

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 IC 50 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 IC 50 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 IC 50 of 5.9 nM at the DAT and K i s of 454 nM and 113 nM at the NET and 5-HTT, respectively, was the most potent and DAT selective analog. Molecular modeling study suggested that the rigid conformation of the isoxazole side chain in 4a-h might play an important effect on their low DAT binding affinities.

The synthetic and therapeutic expedition of isoxazole and its analogs

“…22) surprisingly did not increase the locomotor activity that could be due to lack of brain penetration. Similarly, Jin et al (2008) synthesized a series of 2β-[3ʹ-(substituted benzyl)isoxazol-5-yl]-and 2β-[3ʹ-methyl-4ʹ-(substituted phenyl) isoxazol-5-yl]-3β-(substituted phenyl)tropanes. These compounds were evaluated for affinities at monoamine (dopamine, serotonin and norepinephrine) transporters for the treatment of cocaine abuse.…”

Fluorine-18 Radiolabeled PET Tracers for Imaging Monoamine Transporters: Dopamine, Serotonin, and Norepinephrine

“…[90] This new class of 3β-phenyl tropanes has been exploited extensively in the search for therapeutics to treat cocaine addiction[10,11,91–95] and hundreds of compounds have already been reported in the past[96] and more continue to be reported to this day. [97,98] The structures of some of the first 3β-phenyl tropane compounds prepared, 7 – 12 , are shown in Fig 2 and Table 1. [90–92,99] The high affinity of these compounds for the DAT naturally made them candidates for use as PET tracers when labeled with 11 C as they can all be labeled on either the N -methyl group or the methyl ester.…”

Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters

“…The information was used as an indication of the compound’s potential ability to inhibit uptake of the DA, 5-HT, and norepinephrine (NE) neurotransmitters. Over the last decade, we and others have synthesized a large number of 3-phenyltropane analogues with 3β-phenyltropane-2β-carboxylic acid methyl ester (WIN35,065-2, 2 ) as the lead compound, and evaluated them for binding at monoamine transporters in order to identify the key structural features required for potent and selective monoamine transporter inhibitors 6, 25-34. Generally, the overall tropane configuration, the substituents and substitution pattern on the 3-aromatic ring, the nature of the 2β-subsitituents, and the N-substitution are all important for the ligand recognition site interaction.…”