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. As we had previously seen with compound CTDP-30640, the effects of compound CTDP-31345 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 CTDP-30640 or CTDP-31345 - 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 CTDP-30640 and CTDP-31345 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) demonstrate the validity of our pharmacophore drug design model, our molecular drug design procedures, and our pro-drug medication development strategy. 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 a 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. Further experiments with CTDP-32476 to fully characterize its anti-addiction potential are planned. In addition, during the present reporting period we began to work on modafinil as a potential anti-addicton pharmacotherapeutic compound.
|Xi, Zheng-Xiong; Gardner, Eliot L (2008) Hypothesis-driven medication discovery for the treatment of psychostimulant addiction. Curr Drug Abuse Rev 1:303-27|
|Gardner, Eliot L (2008) Use of animal models to develop antiaddiction medications. Curr Psychiatry Rep 10:377-84|