Current Topics in Medicinal Chemistry - Volume 6, Issue 17, 2006

Neurotransmitter transporters can be divided into two types: the vesicular transporters mediating the uptake and storage of neurotransmitters in vesicles in the presynaptic terminal and two families of membrane-bound transporters responsible for the transport of neurotransmitters from the synaptic cleft back into the presynaptic terminal or glia cells. One of these families, the Na+/Cl--dependent transporters, contains transporters mediating the synaptic reuptake of the monoamines norepinephrine, dopamine and serotonin and the major inhibitory neurotransmitters γ-aminobutyric acid (GABA) and glycine, and other transporters in this family have creatine, taurine and proline as their substrates. The other transporter family consists of five Na+-dependent excitatory amino acid transporters responsible for the synaptic reuptake of glutamate, the major excitatory neurotransmitter in the mammalian CNS. Being essential regulators of the synaptic activity in these important neurotransmitter systems, the membrane-bound neurotransmitter transporters constitute highly interesting targets for pharmacological intervention in a wide range of psychiatric and neurological disorders. Drugs targeting transporters are already being administered in the clinic for depression, attention-deficit hyperactivity disorder (ADHD), obesity and epilepsy and as smoking cessation aids. The present issue of Current Topics in Medicinal Chemistry is focused on medicinal chemistry and pharmacology aspects of ligands targeting membrane-bound neurotransmitter transporters and the possibilities and challenges in connection with the development of novel drugs acting at these transporters or the improvement of already existing ones. The serotonin transporter (SERT) is the key molecular target in the treatment of depression and is thus by far the most successful drug target amongst the neurotransmitter transporters. Selective serotonin reuptake inhibitors (SSRIs) hold significant advantages to older classes of antidepressants, in particular when it comes to their relatively mild side effects. However, the obvious clinical benefits of SSRIs are hampered by their characteristic slow onset of action and the fact that a considerable fraction of depression patients are non-responders to SSRI therapy. In the first review of this issue Moltzen and Bang-Andersen outline the add-on and augmentation strategies currently being pursued in the industry to address these problems through the development of compounds combining SERT inhibition with activities at other monoamine transporters or at various different neurotransmitter receptors [1]. The dopamine transporter (DAT) is a potentially interesting target for a wide range of neurodegenerative and psychiatric disorders, and furthermore it is the key mediator of the psychostimulant effects of recreational drugs such as amphetamine and cocaine. Runyon and Carroll summarize the findings in recent structure-activity studies of 3-phenyltropane, 1,4- dialkylpiperazine, phenylpiperidine and benztropine analogs as well as other classes of DAT ligands [2]. Furthermore, the authors outline the results from studies of DAT inhibitors in non-human primate models of psychostimulant abuse, Parkinson's Disease and ADHD. In their review of monoamine transporter substrates Rothman and Baumann elucidate how the basic inhibitor/substrate properties and the NET/DAT/SERT selectivity profile of the psychostimulant drug determine its pharmacological effects, including its therapeutic potential and its abuse liability [3]. Since equipotent DAT/SERT substrates do not appear to induce the cardiovascular side-effects caused by ‘clean’ serotonin releasers or the psychostimulant side-effects and abuse liabilities characteristic for ‘clean’ dopamine releasers, the authors propose these ligands as candidate drugs for the treatment of cocaine abuse. The GABA and glycine transporters have not attracted nearly as much medicinal chemistry attention as the monoamine transporters. In their review of the GABA transporter (GAT) field, Clausen and colleagues present the structure-activity relationships for different series of conformationally restricted GAT ligands and propose a pharmacophore model for the GAT1 subtype [4]. Several selective GAT1 inhibitors have been published, whereas no truly selective pharmacological tools have been identified for the other three GAT subtypes. Considering the clinical administration of the GAT1-inhibitor tiagabine in epilepsy and the well-established therapeutic potential in augmentation of GABAergic neurosignalling in other disorders like anxiety, convulsive states, pain and sleeping disorders these three subtypes could be interesting as drug targets as well. In addition to having glycine, the co-agonist of the NMDA receptors, as its substrate, the glycine transporter subtype 1 (GlyT1) is co-localized with these receptors in several CNS regions.

Inhibition of serotonin (5-HT) reuptake has been a central theme in the therapy of depression for half a century. Through the years these therapies have improved, particularly with regard to side effects, and today's selective serotonin reuptake inhibitors (SSRIs) constitute a reasonably effective offer for the patients. However, there is still room for major improvement and considering that almost 20%of the population in the western world will experience a depressive period in their lifetime, there is a large need for improved therapies. A large spectrum of targets and strategies are currently being pursued, but so far none of these new approaches have been successful, mainly due to lack of a deeper understanding of the disease biology. Since inhibition of 5-HT reuptake ensures a certain degree of antidepressant efficacy, there has been a large interest in various combinations with serotonin reuptake inhibitors (SRIs) in order to improve on the shortcomings of treatment with SSRIs. Some of these approaches have resulted in marketed antidepressants, eg combinations of SRI with norepinephrine (NE) reuptake inhibition, whereas other approaches are still at an experimental stage. This review attempts to present the current status of these add-on/combination approaches with particular focus on the medicinal chemistry aspects.

The dopamine transporter (DAT) is a target for the development of pharmacotherapies for a number of central disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Lesch-Nyhan disease, attention deficit hyperactivity disorder (ADHD), obesity, depression, and stimulant abuse as well as normal aging. Considerable effort continues to be devoted to the development of new ligands for the DAT. In this review, we present some of the more interesting ligands developed during the last few years from the 3-phenytropane, 1,4-dialkylpiperazine, phenylpiperidine, and benztropine classes of DAT uptake inhibitors as well as a few less studied miscellaneous DAT uptake inhibitors. Studies related to the therapeutic potential of some of the more studied compounds are presented. A few of the compounds have been studied as pharmacotherapies for Parkinson's disease, ADHD, and obesity. However, most of the drug discovery studies have been directed toward pharmacotherapies for stimulant abuse (mainly cocaine). A number of the compounds showed decreased cocaine maintained responding in rhesus monkeys trained to self-administer cocaine. One compound, GBR 12,909, was evaluated in a Phase 1 clinical trial.

Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (α-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions.

For more than four decades there has been a search for selective inhibitors of GABA transporters. This has led to potent and selective inhibitors of the cloned GABA transporter subtype GAT1, which is responsible for a majority of neuronal GABA transport. The only clinically approved compound with this mechanism of action is Tiagabine. Other GABA transporter subtypes have not been targeted with comparable selectivity and potency. We here review a comprehensive series of competitive inhibitors that provide information about the GABA recognition site and summarise the structure-activity relations in a ligand-based pharmacophore model that suggests how future compounds could be designed. Finally, some of the recent results on subtype-characterised competitive inhibitors and recent lipophilic aromatic GABA uptake inhibitors are reviewed.

Clinically utilized antipsychotic agents share as a common mechanism the ability to antagonize dopamine D2 receptors and it is widely assumed that this activity contributes to their efficacy against the positive symptoms of schizophrenia. The efficacy of currently marketed antipsychotic agents on the negative and cognitive symptoms of this disease, however, is not optimal. One alternate hypothesis to the “dopamine hypothesis” of schizophrenia derives from the observation that antagonists of NMDA receptor activity better mimic the symptomatology of schizophrenia in its entirety than do dopamine agonists. Findings from this line of research have led to the NMDA receptor hypofunction (or glutamate dysfunction) hypothesis of schizophrenia, which complements existing research implicating dopamine dysfunction in the disease. According to the NMDA receptor hypofunction hypothesis, any treatment that enhances NMDA receptor activity may prove useful for the treatment of the complex symptoms that define schizophrenia. This idea is now supported by numerous clinical studies that have reported an efficacious response following treatment with activators of the NMDA receptor co-agonist glycineB site. One area of study, aimed at potentiating the NMDA receptor via activation of the glycineB site is small molecule blockade of the glycine reuptake transporter type 1 (GlyT1). Broadly, these efforts have focused on derivatives of the substrate inhibitor, sarcosine, and non-sarcosine based GlyT1 inhibitors. Accordingly, the following review discusses the development of both sarcosine and non-sarcosine based GlyT1 inhibitors and their current status as putative treatments for schizophrenia and other disorders associated with NMDA receptor hypoactivity

This review provides an overview of ligands for the excitatory amino acid transporters (EAATs), a family of high-affinity glutamate transporters localized to the plasma membrane of neurons and astroglial cells. Ligand development from the perspective of identifying novel and more selective tools for elucidating transporter subtype function, and the potential of transporter ligands in a therapeutic setting are discussed. Acute pharmacological modulation of EAAT activity in the form of linear and conformationally restricted glutamate and aspartate analogs is presented, in addition to recent strategies aimed more toward modulating transporter expression levels, the latter of particular significance to the development of transporter based therapeutics.