Nervous system disorders
Allosteric modulation of monoamine transporters – new drug targets in depression

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Current antidepressants modulate monoaminergic neurotransmission via interaction with receptors, transporters and/or metabolism. Drug discovery programs focus mostly on orthosteric drugs that compete with the endogenous ligand for its primary binding site. There is growing interest in allosteric modulators that act via nonorthosteric binding sites. Allosteric modulation of the serotonin transporter is likely to contribute to the therapeutic effect of the selective 5-HT reuptake inhibitor, escitalopram. Therapeutic perspectives of allosteric modulation of monoamine transporters are discussed.

Section editors:

David Sibley – National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA

C. Anthony Altar – Psychiatric Genomics, Gaithersburg, USA

Theresa Branchek – Lundbeck Research, Paramus, USA

Introduction

The aetiology and pathophysiologiy of psychiatric disorders such as depression are not well understood. Monoaminergic [serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE) and dopamine (DA)] dysfunction is a common feature, and the currently used antidepressants modulate monoaminergic neurotransmission via interaction with monoamine receptors, transporters and/or metabolism. However, there are still major unmet needs for increased efficacy and reduced time to achieve therapeutic effect and improved tolerability. Novel mechanisms as well as continued exploration of monoamine brain pathways are, therefore, being pursued in clinical development programs (Table 1) and in drug discovery strategies for new improved antidepressants [1].

Drug discovery programs that have led to currently used drugs have been focused on the development of the so-called orthosteric (or competitive) antagonists or agonists. Orthosteric drugs compete directly with the endogenous ligand for its primary binding site. However, there is a growing interest in exploring the therapeutic potential of compounds that act via nonorthosteric binding sites, the so-called allosteric modulators, for example for G protein-coupled receptors [2]. Recent findings suggest that allosteric modulation of the 5-HT transporter (SERT) contributes to the therapeutic effect of the selective 5-HT reuptake inhibitor, escitalopram [3]. The experimental evidence and therapeutic relevance of allosteric modulation of the SERT and therapeutic perspectives of allosteric modulation of monoamine transporters are discussed here.

Section snippets

Allosteric modulation

Allosteric modulation is a general and widespread mechanism for the control of protein function. Allosteric modulators bind to regulatory sites that are distinct from the active binding site on the protein and produce conformational changes that will modify the protein function. For example, allosteric regulation is an essential mechanism for inhibition and activation of enzymes involved in metabolism, where control of pathways by their end products implies that some enzymes are regulated by

The monoamine hypothesis of depression

The serendipitous finding that symptoms of depression can be improved by agents that increase the synaptic concentrations of monoamines has led to the adoption of the monoamine hypothesis of depression, which proposes that the underlying biological or neuroanatomical basis for depression is a deficiency of monoamine neurotransmitter systems and that targeting this deficiency would restore normal function in depressed patients. The hypothesis has evolved to include adaptive changes in receptors

Escitalopram

The selective 5-HT reuptake inhibitor citalopram is a racemic mixture of an S(+)-enantiomer (escitalopram) and an R(−)-enantiomer (R-citalopram). R-citalopram is approximately 150-fold weaker inhibitor of 5-HT uptake than escitalopram measured in an in vitro rat brain synaptosome assay [3]. On the basis of these data it was expected that escitalopram at half the dose of citalopram would produce the same clinical effect. Surprisingly, clinical studies showed a superior effect of escitalopram

Allosteric modulation of other transporters

The search for allosteric modulators of monoamine transporters has been very limited and has not been drug targets of major interest for pharmaceutical companies. Their low affinity nature is not attractive for high throughput drug screening procedures. Furthermore, the physiological role of allosteric modulator sites on monoamine transporters under normal and pathological conditions remains to be understood in further details. Selective modulators devoid of affinity for the primary high

Conclusions and future directions

Although allosteric modulation of G-protein coupled receptors (e.g. metabotrophic glutamate (mGluR2), NMDA, AMPA, muscarinic cholinergic (M1 or M4), dopamine D4, 5-HT2C, 5-HT7 and GABAB receptors) is a growing area of interest for drug discovery and drug development [10], little interest has been given to allosteric modulation of monoamine transporters. The evolving experimental support for an allosteric modulatory effect on the SERT contributing to an improved clinical efficacy of the

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