Dual Probes for the Dopamine Transporter and σ₁ Receptors:  Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

Abstract

Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ 1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ 1 receptor antagonist that binds to the DAT (K i ) 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ 1 receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ 1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4′-fluorophenyl)-amine analogues have now been prepared in which the most potent DAT compound, 19 (K i ) 8.5 nM), was selective over serotonin transporter (SERT/DAT ) 94), norepinephrine transporter (NET/DAT ) 63), and σ 1 receptor binding (σ 1 /DAT ) 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170-and 140-fold, respectively) and DAT over NET (219-and 190-fold, respectively) but were essentially equipotent at DAT and σ 1 receptors (10; K i ) 77 and 124 nM, respectively, 17; K i ) 28 and 13 nM, respectively). CoMFA studies at both DAT and σ 1 receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and σ 1 receptors may provide a novel approach toward designing medications for cocaine abuse.

Decreases in Cocaine Self-Administration with Dual Inhibition of the Dopamine Transporter and σ Receptors

“…Of interest, it appears that DAT inhibition is also necessary to avoid the effects of R antagonists on foodmaintained responding. Thus, the present results suggest that the effects of rimcazole analogs on cocaine self-administration result from dual occupancy of the DAT and Rs and that these effects may be selective, suggesting further support for developing these agents as treatments for cocaine abuse (Cao et al, 2003;Katz et al, 2003). The optimal ratio of R to DAT affinity cannot be completely addressed without resolution of the relative contributions to the observed effects of 1 and 2 receptors (see below).…”

Synthesis and Pharmacological Evaluation of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a Cocaine Antagonist, in Rodents

“…Cocaine appears to act as an agonist at σ receptors (14,15), and selective antagonists and antisense oligonucleotides at σ receptors can attenuate an array of cocaine-induced effects in animals (12,14,16,17). Together, these earlier data indicate that σ receptors may serve both as a direct target for cocaine and an indirect modulator of dopamine, and perhaps other monoamine transporters (9,14,(18)(19)(20)(21)(22)(23).…”

“…Alternatively, the dual knockout of dopamine and serotonin transporters can yield promising results with regard to reducing certain behavioral actions of cocaine in mice (6). In addition, select compounds that act at monoamine transporters, such as phenyltropane analogs (i.e., RTI-336 (3β-(4-chlorophenyl)-2β-[3-(4′-methylphenyl)isoxazol-5-yl]tropane hydrochloride, RTI-177 (3β-(4-chlorophenyl)-2β-[3-phenylisoxazol-5-yl]tropane hydrochloride) have been proposed for development as potential replacement therapy for cocaine abuse (7)(8)(9). These findings are consistent with the ability of cocaine to interact not only with dopamine but other monoamine transporters (10).…”

Sigma Receptors and Cocaine Abuse

“…It was hypothesized that -1 receptor antagonism might modulate the DAT mediated cocaine-like effects thereby eliciting a dual pharmacological action, which would support the design of dual acting agents to treat cocaine-abuse. Compound 22 and 25 had high to moderate affinities for both DAT and -1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects [149].…”