Slow-onset long-acting dopamine transport inhibitors for treating drug addiction

National Institute On Drug Abuse

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Abstract

We had previosuly shown that our lead proof-of-concept slow-onset long-acting dopamine transporter (DAT) inhibitor - CTDP30640 - enhances electrical brain-stimulation reward, enhances extracellular dopamine in the reward-related nucleus accumbens locus in the brain, stimulates locomotor activity, and significantly reduces intravenous cocaine self-administration in laboratory rats - all with a very pronounced slow-onset long-acting profile of action. During this same period, we extended our research in this area to include two additional compounds that we designed and synthesized de novo using computer-assisted molecular drug design and a pharmacophore DAT model that we ourselves developed - CTDP31345 and CTDP31346. Because of the high degree of similarity between the chemical structures of CTDP31345 and CTDP31346, a decision was made to run only one of those two compounds through a full range of preclinical animal screening paradigms - namely, CTDP31345. We found that CTDP31345 enhances electrical brain-stimulation reward, enhances extracellular dopamine in the reward-related nucleus accumbens locus in the brain, stimulates locomotor activity, and significantly reduces intravenous cocaine self-administration in laboratory rats - all with a very pronounced slow-onset long-acting profile of action. On a less promising note, we found that CTDP31345 generalizes to cocaine in the drug-discrimination animal behavioral paradigm, produces dramatic locomotor sensitization, and triggers relapse to cocaine-seeking behavior in laboratory rats who have been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. We further found that CTDP31345 itself supports intravenous self-administration, albeit at a much lower rate than cocaine. As we had previously seen with compound CTDP30640, the effects of compound CTDP31345 are additive with those of cocaine. This prompted us to explore the relationship between the fast-onset short-acting opiate heroin and the slow-onset long-acting opiate methadone, the latter of which is well-known to have clinical efficacy as an anti-addiction medication for patients addicted to opiates. We reasoned that investigating the heroin-methadone relationship in our preclinical animal models might shed light on medication development stratgies for cocaine and other psychostimulants. We found that - in contrast to the relationship between cocaine and CTDP30640 or CTDP31345 - methadone pretreatment: 1) dose-dependently inhibited intravenous heroin self-administration with a clear behavioral extinction pattern, 2) dose-dependently inhibited heroin-enhanced brain-stimulation reward, and 3) dose-dependently inhibited heroin-enhanced nucleus accumbens levels of the reward-related and relapse-related neurotransmitter dopamine as measured by in vivo brain microdialysis. This suggests a functional antagonism by methadone of heroin's actions, which may be explained by methadone's ability to produce cellular internalization of the mu opioid receptor. These data suggest that in order to be fully successful, potential anti-cocaine medications should more fully emulate methadone's action - i.e., functionally antagonizing cocaine's actions (perhaps by inducing conformational changes in the dopamine transporter) while at the same time blocking the transporter in a cocaine-like manner (but with slow-onset long-lasting pharmacokinetics) so as to substitute for cocaine and remediate the brain chemical deficiency believed to underlie cocaine hunger and cocaine craving. In addition, we believe that the facts that our compounds CTDP30640 and CTDP31345 show much slower onsets and much longer durations of action (e.g., 96 hours following a single injection) than other DAT inhibitors developed as potential anti-addiction pharmacotherapies (e.g., GBR12909) demonstrate the validity of our pharmacophore drug design model, our molecular drug design procedures, and our medication development strategy. On a purely molecular drug design level, during the reporting period we successfully designed and synthesized new slow-onset long-duration piperidine analogs with increased selectivity for the dopamine transporter, resulting in a new test compound - CTDP32476. During the present reporting period, we found the following: 1) that in vitro ligand binding assays show CTDP32476 to be a potent and selective DAT inhibitor; 2) that CTDP32476 is a competitive inhibitor of cocaine binding to the DAT; 3) that systemic administration of CTDP32476 alone produced a slow-onset, long-lasting increase in nucleus accumbens extracellular dopamine; 4) that systemic administration of CTDP32476 alone produced a slow-onset, long-lasting increase in locomotion; 5) that systemic administration of CTDP32476 alone produced a slow-onset, long-lasting increase in electrical brain-stimulation reward; 6) that drug-naive rats do not self-administer CTDP32476; 7) that, in substitution testing, cocaine self-administration rats display a progressive reduction in CTDP32476 self-administration with an extinction pattern of drug-taking behavior, suggesting significantly lower addictive potential than cocaine; 8) that pretreatment with CTDP32476 inhibits cocaine self-administration; 9) that pretreatment with CTDP32476 inhibits cocaine-associated cue-induced relapse to drug-seeking; 10) that pretreatment with CTDP32476 inhibits cocaine-enhanced extracellular nucleus accumbens dopamine. These findings suggest that CTDP32476 is a unique DAT inhibitor that not only could satisfy drug hunger through its slow-onset long-lasting DAT inhibitor action, but also render subsequent administration of cocaine ineffectual - thus constituting a novel and unique compound with translational potential as an agonist therapy for treatment of cocaine addiction. In addition, during the present reporting period we studied modafinil as a potential anti-addiction pharmacotherapeutic compound. () Modafinil (()MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We previously reported a series of ()MOD analogs, of which JJC8-016 was selected for further development. JJC8-016 and R-MOD were then evaluated for binding across 70 receptors, transporters, and enzymes. Although at a concentration of 10M, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D2-like, and sigma-1 receptors. R-MOD was more selective, but had much lower affinity at the DAT than JJC8-016. In rats, systemic administration of R-MOD alone (1030 mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, whereas JJC8-016(1030 mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, whereas R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off-target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.