Novel N-Substituted 3α-[Bis(4‘-fluorophenyl)methoxy]tropane Analogues:  Selective Ligands for the Dopamine Transporter

Abstract

A series of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3 alpha- (diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (Ki range = 8.5-634 nM) and blocked dopamine uptake (IC50 range = 10-371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4"-phenyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered.

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

“…The fundamental obstacle has been that compounds that bind to the DAT most often have pharmacologies similar to cocaine. However, previous studies demonstrated that among analogs of BZT are compounds with affinity at the DAT and different magnitudes of cocaine-like effectiveness in behavioral assays (Agoston et al, 1997;Katz et al, 2004). These findings suggest that altering the chemical structure of drugs acting at the DAT may reduce intrinsic cocaine-like effects.…”

“…The BZT analog JHW007 had a relatively high DAT affinity (23.3 nM) (Agoston et al, 1997) and inhibited DA uptake (IC 50 ϭ 24.6 Ϯ 1.97 nM). The ex vivo displacement of [ 125 I]RTI-121 by JHW007 was dose related, with no plateau apparent at 270 min after injection (Fig.…”

“…We have previously demonstrated that JHW007 has a high selectivity for the DAT relative to other monoamine transporters (Agoston et al, 1997) and have also evaluated the binding of JHW007 to other targets (Katz et al, 2004). Among the binding sites examined, JHW007 had a high affinity for -binding sites, and actions at these sites have been noted to influence the effects of cocaine (Menkel et al, 1991).…”

“…The drugs used in the present studies were as follows: (Ϫ)-cocaine hydrochloride (Sigma/Aldrich, St. Louis, MO), JHW007, N-(nbutyl)-(bis-fluorophenyl)methoxytropane, AHN2005, N-allyl-(bisfluorophenyl)methoxytropane (Agoston et al, 1997), and […”

“…However, others have indicated that DAT occupancy is not related to behavioral activity in a simple way (Rothman et al, 1992;Vaugeois et al, 1993). To further study potential mechanisms for differences between cocaine and BZT analogs, we compared the in vivo binding to the DAT of cocaine and an analog of BZT, JHW007 (Agoston et al, 1997), and related those effects to behavioral activity. In the process, we found that JHW007 had in vivo affinity for the DAT and could antagonize the effects of cocaine, which are unprecedented findings among DAT ligands.…”