We had previosuly shown that our lead proof-of-concept slow-onset long-acting dopamine transporter (DAT) inhibitor - CTDP-30640 - 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 three additional compounds that we designed and synthesized de novo using computer-assisted molecular drug design and a pharmacophore DAT model that we ourselves developed - CTDP-31345, CTDP-31346, and CTDP-32476. Because of the high degree of similarity between the chemical structures of CTDP-31345 and CTDP-31346, a decision was made to run only one of those two compounds through a full range of preclinical animal screening paradigms - CTDP-31345. We found that CTDP-31345 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 CTDP-31345 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 has been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. We further found that CTDP-31345 itself supports intravenous self-administration, albeit at a much lower rate than cocaine. We further found that while the effects of compound CTDP-30640 are additive with those of cocaine, suggesting a common mechanism of action, the effects of the compound CTDP-31345 are not additive with those of cocaine, suggesting that the phenyltetraline chemical series may yield more useful compounds than the indanamine chemical series. These data show that the new follow-on slow-onset long-lasting DAT inhibitor CTDP-31345 mimics cocaine's actions in multiple animal models relating to drug addiction, but with pronounced slow onset and pronounced duration of action. Our compounds 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., GBR-12909), thus demonstrating the validity of our pharmacophore model, our molecular drug design procedures, and our pro-drug medication development strategy. However, the potential utility of such dramatically slow-onset and long-acting DAT inhibitors as anti-addiction, anti-craving, and anti-relapse medications remains to be determined. We therefore initiated an entirely new series of experiments during this reporting period - contrasting the effects of methadone superimposed upon heroin with the effects of CTDP-31345 upon cocaine, in the same battery of multiple animal models relating to drug addiction. We found that methadone acts as a competitive functional antagonist of heroin. And, while not yet fully completed, these experiments show that compound CTDP-31345 has more pronounced blocking effects on cocaine's actions than CTDP-30640. The fact that CTDP-30640 produces dramatic locomotor activation, dramatic behavioral sensitization, and clear triggering of relapse to drug-seeking behavior makes the indanamine chemical series a poor template upon which to built potential anti-psychostimulant therapeutic agents. On a purely molecular drug design level, during the reporting period we also successfully designed and synthesized new slow-onset long-duration methylphenidate analogs with increased selectivity for the dopamine transporter - resulting in our new test compound CTDP-32476. Preliminary experiments with CTDP-32476 suggest that it may have potential utility as an effective anti-addiction pharmacotherapy for psychostimulant addiction.
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