Medications Discovery Research Branch
Clinical Psychopharmacology Section
Overview
From the broadest perspective, the scientific program of the CPS is dedicated to the elucidation of the neurochemical mechanisms underlying the effects of drugs of abuse, and using this knowledge, to develop new medications for treating substance abuse disorders. Our research program is currently focused in two areas: opioid and stimulant pharmacology, each of which will be discussed below.
Current Research Areas & Future Directions
Stimulant Pharmacology
Neurochemical sequalae of chronic stimulant administration. At a time (1991) when most cocaine research focused on dopamine, we began to test the hypothesis that chronic cocaine administration produces serotonergic deficits in rodents, primarily using neuroendocrine challenge methods. Our work demonstrated that chronic cocaine strikingly altered both presynaptic and postsynaptic serotonergic function. A key finding to emerge from this work was that chronic cocaine-induced changes in the serotonin system were similar to changes observed in humans with major depression (Biol. Psychiatry 44: 578-591, 1998), supporting clinical observations of major depressive symptoms in recently abstinent cocaine addicts. Based on our findings, along with reports of chronic-stimulant induced dopaminergic deficits, we proposed the “dual deficit model” of stimulant addiction. We hypothesize that chronic stimulant addiction creates a dual deficit of both the dopamine and serotonin system. A direct prediction of the dual deficit model is that a medication that increases both DA and 5-HT, but not one or the other, will be an effective treatment for stimulant dependence (see below). We plan to extend these studies to chronic methamphetamine administration, where, in preliminary studies, we’ve observed similar presynaptic serotonergic deficits, in the absence of significant serotonin depletion.
Dual DA and 5-HT releasers as treatment agents for stimulant addiction. Based on our work developing the dual deficit model and on clinical observations with combined DA/5-HT releasing agents (phentermine/fenfluramine), we first explored, starting in 1993, the effect of DA and 5-HT releasing agents, alone and together, in various models of stimulant addiction. Major findings from that work included the following: a) co-administration of phentermine and fenfluramine increased both extracellular DA and 5-HT; b) the serotonergic component reduces the stimulant effects of dopaminergic component; c) phentermine suppressed cocaine self-administration in rhesus monkeys, with and without fenfluramine; d) the phentermine/fenfluramine combination acts as a reward-neutral agent both in rats and humans. These findings led us to propose that a single molecular entity that released both DA and 5-HT would be a non-stimulant, reward-neutral agent that would, nevertheless, suppress drug-seeking behavior. Because certain releasing agents have significant adverse effects (cardiac valvulopathy, pulmonary hypertension, neurotoxicity), we conducted several studies to determine probable mechanisms for these adverse effects. A major finding of this work is that fenfluramine-associated cardiac valvulopathy is likely due to the 5-HT2B receptor agonist activity of norfenfluramine (Circulation 102:2836-2841, 2000). Based on these studies, we felt that it would be possible, using non-amphetamine structures, to develop dual DA/5-HT releasers devoid of significant adverse effects. In collaboration with Dr. Bruce Blough (funded by NIDA grant 2R01DA012970-04) we have evaluated hundreds of compounds. Our lead compound (PAL-287) is a non-amphetamine that releases DA and 5-HT in vitro and in vivo, is not neurotoxic, has minimal stimulant activity, is not self-administered by monkeys, and suppresses cocaine-self administration in monkeys. PAL-287 provides proof-of-principle for the use of dual 5-HT/DA releasing agents in the treatment of stimulant addiction (JPET 314(3):1002-12, 2005). These studies are on-going, and we are currently trying to identify PAL-287-like agents with negligible activity at the 5-HT2B receptor.
Long-acting dopamine uptake inhibitors as treatments for stimulant addiction. We began our research on long-acting, slowly dissociating, DA uptake inhibitors as potential treatment agents for stimulant addiction in 1989, choosing GBR12909 as a proof-of-principle compound. In a collaborative effort (Kenner Rice, John Glowa, Michael Baumann and others), we showed that GBR12909 attenuated the ability of cocaine to elevate extracellular DA and decreased cocaine self-administration in rhesus monkeys. In collaboration with Dean Wong, we showed, using PET methods, that doses of GBR12909 which suppress cocaine self-administration in non-human primates substantially occupy DA transporters and that GBR12909 attenuates amphetamine-induced striatal dopamine release, as measured by [11C]raclopride continuous infusion, and also blocks methamphetamine-induced increases in extracellular DA in rats. To address potential problems of medication non-compliance, we were the first to develop a long-acting depot form of GBR12909 (GBR-decanoate, U.S. Patent 6,387,389, issued May 14, 2002). A single injection of this compound almost completely eliminated cocaine self-administration by rhesus monkeys for 30 days and blocked methamphetamine-induced DA release for two weeks in rats. NIDA conducted phase-1 type clinical trials with GBR12909 but had to discontinue them because of GBR12909-induced increases in the QTc interval. Working with Dr. Rice’s group, starting, in 1989 and continuing to the present time, we’ve collaborated on an extensive and productive structure-activity study of GBR12909 congeners, as well as other long-acting non-selective biogenic amine transporter ligands. We also plan to screen a number of GBR analogs at the cardiac HERG channel in order to identify other GBR-type compounds with a lower risk if cardiovascular toxicity.
Allosteric modulators of biogenic amine transporters. Our section devotes time and resources to collaborative efforts with medicinal chemists developing novel biogenic amine transporter agents. Our primary collaborator in this effort is Dr. Rice’s group, with most of the effort devoted to structure-activity studies of GBR12909 analogs. From time-to-time we also work with other medicinal chemistry groups in this area. An interesting theme to emerge from our recent efforts is the identification of allosteric modulators of the DAT and SERT. For example, we identified SORI-9804 as a partial inhibitor of DA uptake and DA transporter binding (Synapse 43:268-274, 2002). In subsequent studies we identified SoRI-6238 (Synapse 53:176-183, 2004) and a GBR12909 analog, 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (JPET 314:906-915, 2005) as allosteric modulators of SERT. In subsequent studies, we plan to examine other GBR12909 analogs for allosteric effects and perhaps work with mutant SERT transporters to identify the binding pocket for these allosteric modulators.
Opioid Pharmacology
Developing mu agonist/delta antagonist compounds. The growing abuse of prescription narcotic analgesics emphasizes the need to develop effective analgesics that do not produce tolerance and dependence. Although this has been a goal of narcotic research for the last century, the finding that co-administration of a delta antagonist with a mu agonist prevents tolerance and dependence provided a pathway to designing an analgesic that does not produce tolerance and dependence. Schiller and associates demonstrated that a single molecule, DIPP-NH(2)[Psi], that is a mu agonist/delta antagonist, also produced mu-mediated antinociception without producing tolerance and dependence. Peptidergic compounds generally suffer from poor systemic availability and difficulties penetrating the blood brain barrier. Thus, in collaboration with Dr. Ananthan (Southern Research Institute), we sought to identify non-peptide mu agonist/delta antagonists. After several years effort, we’ve identified SoRI-20411 (4-chlorophenylpyridomorphinan) as perhaps one of the first non-peptide mu agonist/delta antagonist (J Med Chem 47:1400-1412, 2004). This agent is a potent delta antagonist and a moderate potency partial agonist at mu receptors similar to morphine, which has an EC50 of 290 nM and an Emax of 32%. Unfortunately, the compound is only active after i.c.v adminstration. However, it produces a dose-dependent analgesia that is reversed by pretreatment with beta-FNA. Importantly, chronic administration of SoRI-20411 did not produce tolerance (Fig. 20). Unpublished experiments suggest that chronic administration of SoRI-20411 produces little physical dependence. In the future studies, we hope to optimize this compound to produce higher efficacy and systemic activity.
Studies of Salvinorin A. Our laboratory participated in the recent discovery that the hallucinogenic compound, salvinorin A, is a potent and selective kappa opioid receptor agonist (Proc Natl Acad Sci U S A 99:11934-11939,, 2002). This finding excited considerable interest in part because salvinorin A is the first opioid compound that lacks a nitrogen group. As such, it represents a novel template for structure-activity studies and the possibility of developing opioid compounds with novel properties. We therefore initiated a collaborative effort with Dr. Prisinzano (University of Iowa) to explore the structure-activity of the neoclerodane diterpenes (J Med Chem 48:4765-4771, 2005). Our initial results were quite interesting. Compound 13 in the Harding paper, now known as herkineum (HERK) showed a remarkable increase of potency at the mu receptor. HERK was also a moderate potency full efficacy mu agonist as assessed in the [35S]-GTP-g-S binding assay. The EC50 of morphine is about 60 nM in this assay. This work is on-going, and we intend to follow-up on observations that certain salvinorin A analogs may be allosteric modulators of the mu opioid receptor.
Studies of opioid tolerance and dependence. The mechanisms underlying opioid tolerance and dependence are of great interest and consequently have been intensively studied for decades. At the cellular level, chronic drug exposure leads to changes in receptor-effector signaling. However, these mechanisms alone can’t explain the extraordinary levels of tolerance and dependence that can occur with chronic morphine administration. At the whole animal level, chronic morphine administration produces counter adaptations to maintain homeostasis, including activation of neuronal circuits that oppose the actions of morphine, as well as the release of anti-opiate peptides. In past years, our efforts in this area focused on the role of anti-opiate peptides in maintaining homeostasis. More recently, we’ve conducted experiments that examine chronic morphine-induced changes in the mu opioid receptor and G proteins in CHO cells expressing the cloned human mu receptor. A number of projects are ongoing. A particular iinterest at the present time is the effect of chronic opioid treatment on the expression of Ga12, a G protein involved in the regulation of cell growth (JPET, 2005, in press).
Section Chief and PI
Richard B. Rothman M.D., Ph.D.
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Medications Discovery Research Branch
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