5-HT₆ Receptor Ligands as Antidementia Drugs

Publisher Summary

This chapter describes the most current research on 5-HT₆ mechanisms for attenuating dementia, the status of drugs in clinical development, and controversial issues of 5-HT₆ drug efficacy, most notably the contradictory procognitive data for both 5-HT₆ antagonists and agonists. There are three main approaches that are conceived for antidementia drugs: those that are curative, which actually reverse pathology and brain dysfunction causing dementia; those that are palliative, which delay the progression of disease but do not cure it; and preventative treatments, which avert pathological changes but are ineffective when pathology has already occurred. 5-HT₆ ligands have many potential applications, improving not just long-term memory but also attention, working memory, and behavioral issues, such as depression (behavioral and psychological symptoms of dementia (BPSD)), and many promising 5-HT₆ ligands are being investigated either preclinically or via human trials. So far, most 5-HT₆ ligands completing phase I clinical trials have been well tolerated with minimal side effects, and what remains to be seen is the extent of their clinical efficacy in ameliorating dementia progression.

Introduction

Age-related dementia is a huge public health issue that will undoubtedly increase along with the average age of the world's population. Because of the huge financial and emotional burdens dementia causes, pharmaceutical, biotechnology, and academic labs are continually increasing their efforts toward effective therapies using a wide range of targets. Three main approaches have been conceived for antidementia drugs: those that are curative, which actually reverse pathology and brain dysfunction causing dementia, those that are palliative, which delay progression of disease but do not cure it, and preventative treatments, which avert pathological changes but are ineffective when pathology has already occurred.

Despite the huge impetus for breakthroughs, only a few drugs are currently approved for Alzheimer's patients, and almost all of them have the same mechanism of acetylcholinesterase inhibition, which may only be palliative and not curative. Pharmaceutical companies have so far been wholly unsuccessful in bringing to market a disease-modifying therapy for many reasons: mainly because of the many heterogeneous causes of neurodegeneration, but also because of the many unforeseen, toxic side effects of drugs that reverse or block putative pathological pathways such as amyloid processing. Pharmaceutical researchers are currently revisiting palliative therapies as less risky avenues of drug development. 5-HT₆ ligands are attractive propositions for treating dementia for several reasons: (1) almost all 5-HT₆ antagonists have been shown to improve memory performance in aged or cholinergically compromised animals (Mitchell and Neumaier, 2005); (2) 5-HT₆ antagonists appear to have little toxicity or negative side effects on physiology or brain function (Upton et al., 2008); (3) 5-HT₆ receptors are found almost wholly in the brain, and thus “most antagonists” are inactive on peripheral targets, decreasing chance of side effects (Geldenhuys and Van der Schyf, 2009). (4) Since 5-HT₆ antagonists improve memory via a different mechanism than current dementia treatments, they can be used as adjunct treatments. A final emerging, although not yet validated, reason for developing 5-HT₆ drugs is the possibility of curative as well as palliative actions, and this will be addressed later in this chapter.

Despite the above-mentioned positive attributes relatively few 5-HT₆ antagonists have progressed to clinical trials. This chapter will review the most current research on 5-HT₆ mechanisms for attenuating dementia, the status of drugs in clinical development, and controversial issues of 5-HT₆ drug efficacy, most notably the contradictory procognitive data for both 5-HT₆ antagonists and agonists.

5-HT₆ receptors are found in many brain regions and affect many neurotransmitter systems including acetylcholine, norepinephrine, dopamine, glutamate, and GABA (Mitchell and Neumaier, 2005). Because they are most abundantly expressed in GABAergic neurons of the striatum, nucleus accumbens, cortex, and hippocampus (Roberts et al., 2002), 5-HT₆ receptors likely modulate cognition via GABAergic signaling in basal ganglia and limbic circuits.