Progress in the Search for New Dopamine Transporter Inhibitors

Abstract

In the present review, we provide a comprehensive summary of recent pharmacological studies on dopamine transporter (DAT) inhibitors, which are potential treatments for neurodegenerative and psychiatric disorders. Extensive structure-activity relationship studies have identified numerous tropane-based ligands with high affinity and selectivity for the DAT or with high affinity to the DAT and other monoamine transporters (dual and triple monoamine reuptake inhibitors). The review covers advances in the field in past fifteen years. Among the described compounds, many appear to be promising drug candidates, while other may serve as valuable tools for research or as prototypes for new classes of selective DAT inhibitors. Special attention is being paid to separation of the DAT inhibition from NET and SERT inhibition.

Development and validation of an LC‐ESI‐MS/MS method for the quantification of D‐84, reboxetine and citalopram for their use in MS Binding Assays addressing the monoamine transporters hDAT, hSERT and hNET

“…Thus, a wide variety of compounds from different structural classes (Gryzło, Zaręba, Malawska, Jakubowska, & Kulig, 2015;Singh, 2000), like tropane (Carroll et al, 1991;Carroll et al, 1992), benztropine (Agoston et al, 1997;Newman, Allen, Izenwasser, & Katz, 1994) (Hsin et al, 2002;Rothman et al, 1993;Van der Zee, Koger, Gootjes, & Hespe, 1980) have been synthesized and tested for their selectivity as DAT inhibitors. This led to the identification of the (+)-R,R enantiomer of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-ol [(R,R)-D-84, (R,R)-1, see Figure 1) as a highly selective and highly potent DAT inhibitor (Ghorai et al, 2003).…”

“…This apparent lack of selective DAT inhibitors that are expected to possess a high potential in the treatment of cocaine dependence has spurred an intensive search for these compounds (Ritz, Lamb, Goldberg, & Kuhar, ; Wilcox, Paul, & Woolverton, ). Thus, a wide variety of compounds from different structural classes (Gryzło, Zaręba, Malawska, Jakubowska, & Kulig, ; Singh, ), like tropane (Carroll et al, ; Carroll et al, ), benztropine (Agoston et al, ; Newman, Allen, Izenwasser, & Katz, ) and piperazine derivatives such as 1‐{2‐[bis(4‐fluorophenyl)methoxy ethyl}‐4‐(3‐phenylpropyl)piperazin (GBR 12909) and 1‐[2‐(diphenylmethoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine (GBR 12935) (Hsin et al, ; Rothman et al, ; Van der Zee, Koger, Gootjes, & Hespe, ) have been synthesized and tested for their selectivity as DAT inhibitors. This led to the identification of the (+)‐ R , R enantiomer of 4‐(2‐benzhydryloxyethyl)‐1‐(4‐fluorobenzyl)piperidin‐3‐ol [( R , R )‐D‐84, ( R , R )‐ 1 , see Figure ) as a highly selective and highly potent DAT inhibitor (Ghorai et al, ).…”

Determination of the enantiomeric purity of the selective dopamine transporter inhibitor (+)‐R,R‐4‐(2‐benzhydryloxyethyl)‐1‐(4‐fluorobenzyl)piperidin‐3‐ol

“…4 In addition to their potential for therapy of cocaine addiction, such compounds are also of interest as pharmacological tools. Many groups addressing the structure-activity relationships of DAT ligands have synthesized huge numbers of compounds with a broad variety of structural motifs, 5,6 such as tropane derivatives, 7,8 benztropine derivatives, 9,10 or piperazine derivatives, such as 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-(3-phenylpropyl)piperazin (GBR 12909) and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) [11][12][13] and corresponding analogs derived from these selective DAT inhibitors, to name only a few. Despite the enormous efforts in the search for DAT ligands, no highly potent and selective compounds that may serve as reporter ligands to label DAT binding sites are commercially available to date.…”