2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes:  Potent Non-Nitrogen Inhibitors of Monoamine Transporters

Abstract

Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing and stimulant properties have been associated with its propensity to bind to monoamine transporter systems. It has generally been assumed that the amino function on monoamines is a requirement for binding to monoamine transporters. In particular, the 8-amino function on the tropane skeleton of cocaine and cocaine analogs has been assumed to provide an ionic bond to the aspartic acid residue on the dopamine transporter (DAT). We have prepared the first 8-oxa analogs of the 3-aryltropanes (WIN compounds) and have found that the 3 beta-(3,4-dichlorophenyl) (6g) and 3 alpha-(3,4-dichlorophenyl) (7g) analogs are particularly potent (IC50 = 3.27 and 2.34 nM, respectively) inhibitors of the dopamine transporter. We now describe the synthesis and biology of the family of 2-carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes and demonstrate that an amino nitrogen is not required for binding to the DAT.

Anti-hyperactivity medication: methylphenidate and amphetamine

“…It has long been thought that the nitrogen atom is needed for amine-containing drugs to bind to the biological target, 5 but Madras and colleagues have recently shown that the nitrogen atom may be replaced by either an oxygen atom 6,7 or a carbon atom (BK Madras et al, to be published), and the cocaine-like drugs will still selectively block the dopamine transporter target in vitro. (Although the nitrogen and oxygen atoms each have lone pair electrons which can form a hydrogen bond with the dopamine transporter, 5,7 the carbon atom does not, thus raising considerably interesting theoretical problems as to how such carbon-based molecules bind to the dopamine transporter.…”

“…Thus, amphetamine has two forms, (+)-and (−)-, while methylphenidate has two asymmetric carbon atoms, resulting in four forms, wherein the mixed form (±)-threo-methylphenidate is used clinically. Although each stimulant contains a nitrogen atom which can bond to the dopamine transporter target, Madras and colleagues have shown that the nitrogen atom can be replaced by an oxygen atom 6,7 or a carbon atom (Madras et al, to be published) while still retaining the drug's potency in vitro.…”

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

“…Similarly modified methylphenidate analogs displayed DAT affinities indistinguishable from methylphenidate itself (Meltzer et al, 2003). In contrast, replacement of the basic tropane nitrogen with a neutral functional group (e.g., N-formyl group or oxygen atom) in the benztropine class of DAT inhibitors substantially reduced DAT binding affinity (Agoston et al, 1997;Meltzer et al, 1997;Simoni et al, 2001).…”

“…On the other hand, a similar 8-oxa modification of WIN 35,428 sharply reduced binding affinity and DUIP at the DAT. This deficit was fully compensated for by further replacing the p-fluoro substituent of the C-3 phenyl group with a chloride atom (Madras et al, 1996) and further improved with a 3,4-dichloro substitution (Meltzer et al, 1997). Elimination of hydrogen bonding potential at the 8-position of WIN 35,428 by substitution of a carbon atom also substantially compromised affinity at the DAT.…”

Computational and Biochemical Docking of the Irreversible Cocaine Analog RTI 82 Directly Demonstrates Ligand Positioning in the Dopamine Transporter Central Substrate-binding Site

“…Overlap of high affinity inhibitor binding with the S1 site is supported by biochemical studies (38,44,47,55) and by recent structures of Drosophila (d) DAT and a LeuT/SERT hybrid co-crystallized with antidepressants (40,56). However, some DA transport inhibitors lack the charged nitrogen necessary to form the salt bridge with Asp-79 (57)(58)(59), suggesting that inhibitor binding can occur without this interaction and thus may not be limited to the S1 pocket (60). This possibility is supported by crystal structures of LeuT complexed at relatively low affinity with several selective serotonin uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in regions that overlap with S2 (16 -18, 56).…”