Novel 4'-Substituted and 4',4''-Disubstituted 3.alpha.-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors

Abstract

A series of 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were prepared as novel probes for the dopamine transporter. These compounds were evaluated in radiolabeled binding assays for the dopamine, norepinephrine, and serotonin transporters. All of these compounds monophasically displaced [3H]WIN 35,428 binding in rat caudate putamen with Ki values ranging from 11.8 to 2000 nM. The most potent compound in this series was 4',4"-difluoro 3 alpha-(diphenylmethoxy)tropane 7c with a Ki = 11.8 nM. All of the compounds inhibited dopamine uptake in rat caudate putamen (IC50 = 24-4456 nM) which correlated significantly (r = 0.907; p > 0.0001) with binding affinities at the dopamine transporter. None of the compounds demonstrated high-affinity binding at the norepinephrine (Ki > 4800 nM) or serotonin (Ki > 690 nM) transporters. Therefore, the most potent dopamine uptake inhibitors in this series were highly selective for the dopamine transporter. Preliminary behavioral studies of several of these analogs (7a-e) suggested that the compounds did not display a cocaine-like behavioral profile, despite their ability to inhibit dopamine uptake. The present data coupled with the observed differences from cocaine in structure-activity relationships suggested that the 3 alpha-(diphenylmethoxy)tropane analogs may be interacting at a different active site than cocaine on the dopamine transporter and that an additional binding domain might be exploited for the identification of potential therapeutics for the treatment of cocaine abuse.

Recognition of Benztropine by the Dopamine Transporter (DAT) Differs from That of the Classical Dopamine Uptake Inhibitors Cocaine, Methylphenidate, and Mazindol as a Function of a DAT Transmembrane 1 Aspartic Acid Residue

“…Within this series, only 4Ј,4Љ-difluoroBZT and GBR-12,909 were unaffected by the mutation with respect to DUIP or binding affinity. These compounds share the 4Ј,4Љ-difluorophenylmethoxy moiety previously demonstrated to provide optimal DAT binding affinity (van der Zee et al, 1980;Newman et al, 1995). Replacement of the N-methyl group of 4Ј,4Љ-difluoroBZT with the charge-neutral N-formyl group, however, dramatically reduced DUIPs at both WT and D79E DAT, and this reduction was 13-fold more severe at the WT DAT.…”

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

“…The major structural difference between the present aryltropanes and cocaine-like DAT inhibitors (e.g., Carroll et al, 1992) resides in the diphenyl-ether substitution on the tropane 2-position, which is a significant substituent of atypical DA uptake inhibitors that are structurally related to BZT (van der Zee et al, 1980;Newman et al, 1995) and the phenylpiperazines (e.g., GBR 12909; van der Zee et al, 1980;Andersen, 1989). Many of the members of those structural groups have various effects atypical of standard DAT inhibitors such as cocaine and methylphenidate.…”

Identification of a Dopamine Transporter Ligand That Blocks the Stimulant Effects of Cocaine

“…Analogs of benztropine (BZT), for instance, have high affinity for the DAT and inhibit DA uptake in vitro. However, these drugs compared with cocaine have reduced effectiveness as behavioral stimulants and generally do not share subjective and reinforcing effects of cocaine in drug-discrimination and self-administration animal models (Newman et al, 1995;Katz et al, 1999;Woolverton et al, 2001). These findings suggest that some structural variants of drugs acting at the DAT may have reduced abuse liability compared with cocaine and a potential approach to the discovery of medications for cocaine abuse.…”