Transporters as Targets for Drug Discovery

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This volume focusses on transporters as targets for drug discovery. A diverse range of topics are covered; from recent advances in the structural biology of transporters and its impact on potential structure-based drug design (Sylte et al.), through a case study of medicinal chemistry drug design (Newman et al.), to the design of PET ligands and their importance in understanding early clinical trial data (Antoni et al.).

The monoamine transporters are the most established drug targets, and as such there are many excellent reviews covering the launched antidepressant selective serotonin uptake inhibitors (SSRIs), selective serotonin and noradrenaline reuptake inhibitors (SNRIs) and TCAs [37]. In this volume we focus rather on more recent developments in the search for second generation monoamine reuptake inhibitors which address the deficits in current marketed drugs. The SSRIs have a good side effect profile however, as antidepressants they suffer from a slow onset of action and significantly, 30-40% of patients do not respond satisfactorily to them. Conversely, although the TCAs are effective antidepressants they have poor selectivity over muscarinic, his-taminic and adrenergic receptors, resulting in cardiovascular, anticholinergic and sedative side effects.

Whitlock et al. describe progress in the discovery of SSRIs, noradrenaline reuptake inhibitors (NRIs), and SNRIs from 2000 to the present day. Whilst Chen et al. focus on recent developments in the search for triple SERT, NET and DAT reuptake inhibitors. The interest in these areas stems not only from the potential for improved antidepressant efficacy and side effect profiles, as has been proposed for the triple reuptake inhibitors [38], but the recognition that by tweaking the transporter profile potential therapies for other diseases associated with neurotransmitter imbalance can be developed. For example, although duloxetine 6 (Fig. 1), a dual SNRI, was initially launched in 2004 for the treatment of major depressive disorder (MDD) [39], since 2004 additional approvals have been granted for pain associated with diabetic neuropathy [40] and fibromyalgia [41], for stress urinary incontinence [42] and generalised anxiety disorder [43]. NRIs have been licensed for the treatment of attention deficit hyperactivity disorder (ADHD), as well as being of interest for the treatment of neuropathic pain. The continuing increase in the number of patents being filed for monoamine reuptake inhibitors reflects the ongoing interest in these transporters as targets for drug discovery.

The monoamine reuptake transporters, and DAT in particular, are also responsible for the stimulant properties of several drugs of abuse such as cocaine and amphetamine. The mechanisms underlying the abuse potential of these drugs remain the subject of debate. The dopamine transporter (DAT) hypothesis of cocaine's behavioral effects was first proposed by Ritz et al. [44] following their observation that there was a positive correlation between the binding affinity at DAT and the potency for self-administration of a variety of monoamine uptake inhibitors. Many studies have subsequently supported the DAT hypothesis, however it is becoming more evident that the elegant simplicity of this hypothesis may hide a more complex reality. For example, DAT knockout mice still exhibit place preference and self-administration of cocaine [45,46]. The interdependency of the monoamine neurotransmission systems and the fact that cocaine also inhibits SERT and NET further complicate interpretation of the in vivo data. Finally, there are non-cocaine based DAT inhibitors which are used clinically which do not show abuse potential and it is one class of these inhibitors, the benztropines (Fig. 3), which forms the subject of a case study in drug discovery by Newman et al. In their chapter they review the current state-of-the-art in our understanding of the mechanisms underlying the abuse potential of this class of drugs.

It is remarkable that despite nearly half a century of use of monoamine re-uptake inhibitors our understanding of their mode of action, cocaine being a case in point, is still limited. Despite advances in our knowledge of the neu-rotransmitter systems at the molecular level, translating this information into predictions for the effect of a given compound in man is still fraught with problems. It is not possible to develop a true animal model for a disease such as MDD since it is questionable whether animals can suffer from a similar illness and we cannot ask the animal for a subjective opinion as to how it feels! This is a problem common to all psychiatric illnesses and hence the challenges associated with developing suitable animal models mean that it is often not until late stage clinical trials that the hypotheses for the therapeutic benefit of reuptake inhibition can be tested. The cost of a compound failing late in clinical development is significant and companies are increasingly looking to incorporate imaging techniques into early clinical trials for CNS drugs to limit late stage attrition rates. In their review Antoni et al. introduce the PET imaging technique and discuss the current state-of-the-art with respect to imaging the transporters. They cover not only the neurotransmitter trans-

Benztropine R1=CH3, R2, R3=H

Benztropine R1=CH3, R2, R3=H

porters but also the ABC transporters, the glucose transporter GLUT and the vesicular monoamine transporter-2. PET imaging cannot increase the likelihood of a compound succeeding in the clinic, but rather allows companies to make faster decisions to stop the development of ineffective compounds. PET imaging can be used to relate drug pharmacokinetics in plasma to receptor occupancy, and subsequently to relate this to clinical efficacy. In the absence of the receptor occupancy information from imaging studies it is difficult to assess whether a lack of clinical efficacy is due to insufficient drug at the desired site of action or due to failure of the mechanistic hypothesis. The translatability of this non-invasive technique provides a link with PET imaging in animal models, thus allowing preclinical evaluation and ranking of new chemical entities to select the most promising to progress into the clinic.

Although there are PET tracers available, there is still much work to be done to identify "ideal" PET ligands for the transporters suitable for use in the clinic. As highlighted by Antoni et al. in their review, "the stringent criteria required for a suitable PET tracer mean that the process of identifying a suitable PET ligand presents as many challenges as the discovery of a new drug".

In addition to regulating monoaminergic chemical transmission, transporters also play a role in controlling synaptic concentrations of amino acid neurotransmitters. Two such transporters for the CNS active amino acid glycine, GlyT1 and GlyT2 from the NSS family were identified in the early 1990s [47-49]. Since that time there has been significant interest in GlyT1 inhibition as a therapy for schizophrenia with the proposed additional benefit of improved cognition. Although there is substantial pharmacological evidence to support this therapeutic hypothesis, clinical proof of concept is yet to be determined. However, a number of interesting compounds have now progressed to clinical trials and hence the validity of GlyT1 as a target for schizophrenia, as well as differentiation between the different structural classes of inhibitors, is likely to be clarified in the next decade. In their review Walker et al. (vide infra) review the current medicinal chemistry landscape for the glycine transporters and report progress towards the identification of subtype selective GlyT inhibitors. Particular emphasis is given to developments in the last 2 years towards the identification of non-amino acid based inhibitors.

A volume on neurotransmitter transporters would not be complete without inclusion of the EAATs. Glutamate is now recognised as the primary excitatory neurotransmitter in the CNS where glutamate synapses mediate the majority of fast excitatory neurotransmission. The glutamatergic synapses are essential for normal development and are involved in synaptic plasticity, learning and memory. Attention has tended to focus on the ionotrophic and metabotrophic glutamate receptors (iGluRs and mGluRs, respectively) as targets for therapy however, the EAATs also play an important physiological role in glutamate neurotransmission by clearing glutamate from the synapse. Bridges et al. describe recent research towards the development of subtype selective EAAT inhibitors and subsequent attempts to better understand the contributions of the different EAAT transporters. The studies to date highlight the neuroprotective role of the EAATs and point towards the use of compounds which enhance glutamate uptake for therapy. The feasibility of this as an approach is yet to be determined, since there is little precedent for developing agents which act as positive modulators of the transporters.

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