5-HT6 Receptor Ligands as Antidementia Drugs
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.
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Pharmacological Models (Anticholinergic and Antiglutamatergic)
One of the hallmarks of Alzheimer's disease, along with amyloid plaque and tau tangle formation, is the attenuation of acetylcholine signaling (Sambeth et al., 2007). Thus, cholinergic antagonists are used to model this deficiency in order to evaluate putative antidementia drugs.
The most predominantly used model of disrupted cholinergic function is scopolamine administration before or after a learning task. Scopolamine, a M1 muscarinic antagonist, causes amnesia in young animals at moderate
Biomarkers of 5-HT6 Receptors’ Antidementia Effects
This section gives an overview of signaling molecules and receptors that have been implicated in 5-HT6 mechanism of action. Since many of these molecules are also associated with learning and memory, it may be possible to predict clinical efficacy with these putative “biomarkers.”
Clinical Studies of 5-HT6 Antagonists
The number of 5-HT6 antagonists in clinical studies is quite large, considering the fact that most drugs currently being developed are curative, and 5-HT6 antagonists’ proposed action is palliative. However, only one Phase II clinical trial of a 5-HT6 antagonist has been reported in detail (Maher-Edwards et al., 2009), and the results show SB-742457 to be as efficacious as donepezil, an acetylcholinesterase inhibitor that is currently the most prescribed drug for Alzheimer's dementia. However,
5-HT6 Agonists
Due to the technical challenges of developing a specific, highly potent 5-HT6 agonist, less is known about neurochemical and behavioral effects of 5-HT6 stimulation. However, in the last 5 years several selective 5-HT6 agonists have been identified and are now in clinical development.
The best studied 5-HT6 agonist is WAY-181187, which, at doses of 3–30 mg/kg s.c., increases GABA release in the hippocampus, as shown via microdialysis, and attenuates stimulated glutamate (Schechter et al., 2008).
Ceiling Effects and Adjunct Therapy
Clinical studies of 5-HT6 drugs have targeted patients with mild-to-moderate dementia. Subject selection of such patients is difficult, since the diagnosis of mild-to-moderate dementia uses tools that do not fully assess different types of cognitive ability. Therefore, the variability of cognitive ability in trial subjects can be quite high, and thus may obscure smaller scale benefits from a treatment. Additionally, the progress rate of disease can also be quite broad. The proposed palliative
Conclusion
Many promising 5-HT6 ligands are currently being investigated either preclinically or via human trials. However, with the current constraints on drug development, including funding, lack of sensitive evaluation tools, and increasing bureaucracy in all stages of research, it is uncertain whether any of these drugs will reach the market. 5-HT6 ligands have many potential applications, improving not just long-term memory, but also attention, working memory, and behavioral issues such as depression
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