Discovery of Drugs to Treat Cocaine Dependence: Behavioral and Neurochemical Effects of Atypical Dopamine Transport Inhibitors

Abstract

Stimulant drugs acting at the dopamine transporter (DAT), like cocaine, are widely abused, yet effective medical treatments for this abuse have not been found. Analogs of benztropine (BZT) that, like cocaine, act at the DAT have effects that differ from cocaine and in some situations block the behavioral, neurochemical, and reinforcing actions of cocaine. Neurochemical studies of dopamine levels in brain and behavioral studies have demonstrated that BZT analogs have a relatively slow onset and reduced maximal effects compared to cocaine. Pharmacokinetic studies, however, indicated that the BZT analogs rapidly access the brain at concentrations above their in vitro binding affinities, while binding in vivo demonstrates apparent association rates for BZT analogs lower than that for cocaine. Additionally, the off-target effects of these compounds do not fully explain their differences from cocaine. Initial structure–activity studies indicated that BZT analogs bind to DAT differently from cocaine and these differences have been supported by site-directed mutagenesis studies of the DAT. In addition, BZT analog-mediated inhibition of uptake was more resistant to mutations producing inward conformational DAT changes than cocaine analogs. The BZT analogs have provided new insights into the relation between the molecular and behavioral actions of cocaine and the diversity of effects produced by dopamine transport inhibitors. Novel interactions of BZT analogs with the DAT suggest that these drugs may have a pharmacology that would be useful in their development as treatments for cocaine abuse.

Introduction

Dopamine (DA) neurotransmission subserves a multitude of normal physiological functions in the central nervous system (CNS), with many factors affecting DA homeostasis. DA neurotransmission is regulated dynamically at the synaptic level by several mechanisms including negative feedback circuits induced by DA receptor occupancy that modulate neuronal activity, as well as DA synthesis. However, termination of the actions of DA by rapidly reducing its synaptic concentrations is critical. This occurs via metabolic degradation pathways, including monoamine oxidase and catechol-oxy-methyl-transferase enzymes, and by DA uptake (Iversen, Iversen, Bloom, & Roth, 2008). DA uptake sites or DA transporters (DATs) are membrane-bound proteins that efficiently transport DA from the extra- to the intra-cellular space and represent the major mechanism for the rapid termination of DA neurotransmission.

One of the most prominent of the diseases that involve dysfunctional DA neurotransmission is Parkinson’s disease (PD) in which degeneration of the DA system leads to a reduction in neurotransmission in dopaminergic terminal areas that are important not only for somatic–motor functions but also for emotional–affective functions (Lees, Hardy, & Revesz, 2009). Indeed some of the typical symptoms of PD involve a difficulty to initiate movements, as well as depression and apathy (Chaudhuri & Schapira, 2009). Drugs that target the DAT, methylphenidate and d-amphetamine, are clinically effective treatments, and genetic variants in the DAT have been implicated in the etiology of attention deficit hyperactivity disorder (ADHD) (e.g., Hahn & Blakely, 2007). A DA component is also involved in other diseases involving emotional and affective functions, including schizophrenia, autism, Tourette’s syndrome, and depression (Meisenzahl, Schmitt, Scheuerecker, & Moller, 2007; Steeves and Fox, 2008, Stein, 2008).

The DAT is also the main target for stimulant drugs of abuse, such as cocaine, amphetamine, methamphetamine, and methylenedioxymethamphetamine (Zhu & Reith, 2008). Stimulant abuse and addiction are recognized to be major public health and socioeconomical issues (see, e.g., Substance Abuse and Mental Health Services Administration, 2007, http://www.oas.samhsa.gov), and research efforts over the last two decades have shed light on the neurobiological basis of cocaine dependence (Kalivas, 2007, Nestler, 2005). And while promising new strategies for the development of medical treatments have been reported (e.g., Kharkar et al., 2008, Newman and Katz, 2009, Runyon and Carroll, 2008, cocaine addiction remains a condition for which effective medical treatments have not yet been identified.

Cocaine acts in the CNS at several pharmacological targets. For example, its local anesthetic effects have been well documented together with its effects on Na⁺ channels (Catterall & Mackie, 2006). However, the main activity contributing to the reinforcing effects of cocaine and its consequent abuse liability involves the blockade of plasma membrane monoamine transporters (see review by Carroll, Howell, & Kuhar, 1999). Although cocaine inhibits the transport of dopamine, serotonin, and norepinephrine from the synapse into nerve terminals, blockade of the DAT is considered the main effect through which the pharmacology of cocaine contributes to its behavioral and reinforcing actions (Kuhar, Ritz, & Boja, 1991; Ritz, Boja, George, & Kuhar, 1989).

It has been hypothesized that drugs blocking the DAT will have reinforcing effects similar to those of cocaine (Kuhar et al., 1991). However, of the several chemical classes of DAT inhibitors synthesized in the past 15–20 years, some have behavioral effects that differ from those of cocaine (Newman & Kulkarni, 2002). Because of these variations in behavioral effects, these “atypical” DAT inhibitors are being actively investigated to find clues that may help in the search for psychostimulant abuse medications.

Agonist or substitution therapies have been successful in the treatment of opioid (Mattick, Breen, Kimber, & Davoli, 2009) and nicotine abuse (Stead, Perera, Bullen, Mant, & Lancaster, 2008). As such, drugs that block the DAT, but with lower abuse potential compared to cocaine, have been the focus of many of the drug discovery programs directed at cocaine-abuse treatments. One of the most studied compounds, GBR 12909 (Fig. 1), which shares some basic pharmacological features with addictive psychostimulants, has preclinical effects suggestive of a clinically effective treatment. Specifically, treatment with GBR 12909 decreases cocaine self-administration in animals, at doses that do not affect the behaviors reinforced with food presentation (see review by Rothman, Baumann, Prisinzano, & Newman, 2008). However, the appearance of cardiovascular effects in clinical trials prevented its further development (Vocci, Acri, & Elkashef, 2005).

Several classes of DAT inhibitors that were tested preclinically for their potential as treatments for stimulant abuse have been reviewed elsewhere (e.g., Kharkar et al., 2008, Meltzer, 2008, Prisinzano and Rice, 2008, Runyon and Carroll, 2008. The present review focuses on analogs of benztropine (3α-diphenylmethoxytropane, BZT, Fig. 1). This parent compound was initially of interest because it shares structural features with both cocaine and GBR 12909 (Fig. 1). Therefore, solely from a structural perspective, BZT and its analogs were of interest. Moreover, though BZT is in clinical use for treatment of early-stage PD for many years, there are only a few case reports of its abuse, mainly related to its anticholinergic effects (see, e.g., Grace, 1997). Finally, Colpaert, Niemegeers, and Janssen (1979) showed that BZT did not fully substitute in rats trained to discriminate cocaine from saline injections. These considerations suggested that BZT analogs could be of interest for cocaine-abuse treatment and may have advantages over DAT inhibitors that share cocaine-like preclinical indications of abuse liability. To pursue this possibility, we initiated a program of synthesis and evaluation of BZT analogs. A comprehensive review of the chemistry of these compounds has been recently published (Newman & Katz, 2008). In this chapter we review preclinical and clinical research that has been conducted on BZT analogs as it relates to the potential of these compounds as medications for cocaine abuse.

• JJC 1-059: N-(3-((3S,5R)-3,5-dimethyl-4-(3-phenylpropyl)piperazin-1-yl) propyl)-4-fluoro-N-(4-fluorophenyl)aniline

• JJC 2-010: 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol

• GBR 12909: 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine

• WIN 35,428: (–)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane

• RTI-371: 3β-(4-methylphenyl)-2β-[3-(4-chlorophenyl)isoxazol-5-yl]tropane

• RTI-121: (–)-2β-carboisopropoxy-3β-(4-iodophenyl)tropane

• RTI-55: 3β-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester

• RTI-31: (–)-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane

• CP 55940: 2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol