Editorial [Hot Topic: Neurotransmitter Transporters Guest Editor: Dr. Anders A. Jensen ]

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.