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showed cardiotoxicity (increases in QTc interval) in phase I clinical trials80 and will not move forward in the clinic, structurally similar analogs of benztropine such as JHW 007 and AHN 2-005 show promise preclinically as potent and selective DAT inhibitors that are not cocaine-like in numerous animal models and attenuate cocaine-induced behaviors.79,81 This unique behavioral profile is proposed to be due to their slow association onto the DAT and long duration of action, and is currently being further evaluated.

Agents that release both DA and 5HT via a DAT and SERT carrier-mediated exchange mechanism (an amphetamine-like action), were proposed to be potential treatment agents for cocaine addiction that would have low abuse liability yet still be able to decrease drug seeking behavior.82 In support of this hypothesis, recent work demonstrated that the dual DA/5HT releaser PAL 287, a naphthylisopropylamine, is not self-administered yet suppresses cocaine self-administration in rhesus monkeys.52 The compounds discussed above target the monoamine transporters, since these are primary proteins through which cocaine and methamphetamine produce their psychostimulant and reinforcing actions. However, additional targets that may be more associated with long-term effects of drugs of abuse on the reward circuitry, and which may provide new targets for treatment of drug relapse have been identified. These are briefly described below.

DA receptor subtypes (D1-like and D2-like) have been targeted for many years as yielding potential medications for the treatment of cocaine abuse.83 Unfortunately, for the most part, these compounds have provided important insight into the roles the D1- and D2-like receptors play in the pharmacology of substances of abuse, but untoward side effects and a lack of efficacy that have limited their potential as medications.84 Recent investigations have demonstrated that selective and high-affinity DA D3 receptor ligands attenuate cocaine seeking behaviors and show promise in animal models of relapse. Furthermore, these compounds do not demonstrate behavioral toxicity associated with other nonselective D2 receptor ligands.85 Promising candidates from the D3 class of compounds are primarily antagonists or partial agonists that fall into a rather narrow SAR profile as recently reviewed.85 Compounds BP 897 (Figure 8), SB 277011, NGB 2904, and PG 01037 (Figure 9) are the 'drugs of choice' for studying the role of the DA D3 receptor in drug abuse, and BP 897 is currently in clinical trials for treatment of psychiatric disorders, including drug abuse.75 Although SB 277011 has a metabolic profile that is unsuitable for clinical use, future analogues are currently under investigation.85 PG 01037 is an analog of NGB 2904 that demonstrates high affinity (Ki = 0.7 nM) for hD3 receptors and greater than 130-fold selectivity over hD2 receptors in vitro, and is also water soluble. Like the other D3 antagonists, PG 01037 is a D3 receptor antagonist in several in vivo models, and attenuates cocaine-induced reinstatement in monkeys without behavioral toxicity (R. Spealman, D. Platt, and A. Newman, unpublished observations). Further investigation into the D3 receptor as a target for psychostimulant abuse medications will determine whether these or other compounds should be developed further.

Both depression and stress promote relapse in drug abusers. The endogenous k-opioid agonist dynorphin has been implicated in modulating stress via the k-opioid receptor system. Thus, k-opioid receptor antagonists have been under development for some time as potential treatments for drug addiction. Recently, JDTic (Figure 9) emerged as a lead compound to test this hypothesis because of its antidepressant effect and efficacy in animal models of drug relapse. Other preclinical studies support the clinical development of this agent and future studies will determine its potential as a cocaine abuse medication in humans.86 Similarly, the ability of corticotropin receptor 1 (CRH1) receptor antagonists to reduce stress and anxiety has led investigators to explore the effect of CRH1 receptor antagonists on cocaine-related behaviors. As reviewed by Gurkovskaya,87 CRH1 receptor antagonists can reduce cocaine self-administration as well as cue-induced cocaine seeking behavior.

Several other nondopaminergic targets are under active investigation as potential targets for drug addiction medication development. One such target is the metabotropic glutamate receptor subtype 5 (mGluR5). Initial studies in rats showed that the selective mGluR5 antagonist MPEP (Figure 9) attenuated cocaine seeking behavior, and that a mGluR5 ko mouse would also not respond for cocaine.88 These initial studies suggested a role for this receptor subtype in the addictive effects of cocaine. Subsequently, efforts in several industrial and academic laboratories have focused on discovering novel high-affinity and selective mGluR5 noncompetitive antagonists/allosteric modulators that have improved bioavailability over MPEP. This has been a formidable challenge, since even small changes in the MPEP structure lead to a loss of activity. One successful modification was the replacement of the 2-methylpyridyl ring of MPEP with a 2-methylthiazole and the minor modification substituting the phenyl ring with the isosteric pyridyl ring system to give the close analog MTEP (Figure 9),89 which has been used for several recent in vivo studies. These and additional mGluR5 antagonists are providing the tools to further elucidate the role of the mGluR5 in drug addiction.90 In addition the mGluR2/3 receptors are also under intensive investigation toward further understanding the roles of these receptors in drug addiction and neuropsychiatric disorders, and the therapeutic potential of allosteric modulation of these receptors has been recently disclosed.91 RGS proteins are another potential target,92 but much research remains to investigate the utility of this family of proteins for developing drug abuse treatment medications.

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