Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

Abstract

In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine-like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure-activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related to the differing pharmacological actions of these compounds, in vivo. These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine-abuse therapeutics.

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

“…3,[12][13][14][15][16] In our initial series of rimcazole analogues, the most potent DAT inhibitor, 1 (K i ) 61 nM), showed moderately potent σ 1 binding affinity (K i ) 97 nM) and was ∼3-fold less potent at SERT (K i ) 219 nM) and 60-fold selective over NET. 11 Several rimcazole analogues (1-4) were evaluated in animal models of cocaine abuse and toxicity.…”

Medication Development for the Treatment of Cocaine Addiction – Progress at Preclinical and Clinical Levels

“…Indeed, this strategy has been at the forefront of medication development for the treatment of cocaine addiction for more than a decade (Rothman and Baumann, 2006;Howell and Kimmel, 2008). To date, many DAT inhibitors have been developed, and several of them have been tested in human clinical trials (Newman and Kulkarni, 2002;Runyon and Carroll, 2006;Rothman et al, 2006Rothman et al, , 2008. Fig.…”

Modulation of the endocannabinoid system: Therapeutic potential against cocaine dependence

“…Thus, increased availability of dopamine for dopamine receptors is believed to mediate most of the reinforcing actions of cocaine, leading to its abuse liability (1,3,23,27). However, cocaine abuse and addiction are processes that go well beyond the pharmacological effects of cocaine on dopamine neurotransmission, so that many other factors, genetic and environmental for example, have been suggested to play a role in the complex of actions that lead from cocaine use to its abuse and addiction (28,29,30,31).…”

“…There is no specific pharmacological therapy available against cocaine's addictive effects, but researchers in the last decades have made progresses in the understanding of the neurobiology underlying cocaine's actions (29,30). Today, different aspects of cocaine abuse and addiction in humans can be modeled and studied in experimental animals.…”