Current Topics in Medicinal Chemistry - Volume 10, Issue 2, 2010

Research in the field of cognition is currently a high priority as the elderly population increases, with a great need to discover and develop new drugs to treat age-related cognitive disorders, including dementias as well as cognitive impairments associated with neuropsychiatric disorders, such as schizophrenia. Various aspects of cognitive dysfunction also occur in association with several CNS disorders, including Parkinson's disease, AIDS-associated dementia, stroke, stress, sleep deprivation, depression, and anxiety. Cognition is a complex set of processes, including attention, perception, emotion, learning and memory, action, and problem solving. Drugs currently approved for use in the treatment of neurodegenerative disorders, such as Alzheimer's disease (AD), include the cholinesterase inhibitors donepezil, rivastigmine, and galantamine, and memantine, a partial agonist at glutamate receptors. Since none of these drugs works particularly well in treating the symptoms of AD, a variety of new drug discovery approaches and chemical entities are currently being explored to identify new cognitive enhancers. This special issue will review a few of the key contemporary targets that are being pursued in discovery research that are either at the late-preclinical stage or are in clinical evaluation to treat cognitive deficits of various CNS diseases. Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated cationic-channels that are highly expressed in the CNS. The α7 and α4/β2 subtypes are involved in cognition and attention, and are highly expressed in brain regions involved in learning and memory, including the hippocampus, thalamus and cortex. nAChRs are involved directly and indirectly in release of neurotransmitters including acetylcholine, dopamine, glutamate and norepinephrine, and in AD and schizophrenia, levels of cortical nAChRs are decreased. In the first review in this issue Haydar and Dunlop review intense drug discovery efforts focused on the development of α7 and α4/β2 nAChR agonists and, more recently, positive allosteric modulators (PAMs) of the α7nAChR as potential therapeutic agents. Histamine H3 receptors (H3R) are expressed predominatly in the brain, localized to the cerebral cortex, amygdala, hippocampus, striatum, thalamus and hypothalamus, where they are expressed on presynaptic terminals and function as inhibitory auto- and hetero-receptors. H3 antagonists increase the release of various neurotransmitters, including histamine, ACh, NE, 5-HT and DA, and have potential utility in treating cognitive deficits associated with various dementias and schizophrenia. In the second review, Raddatz, Tao and Hudkins review the H3R biology and recent drug discovery efforts as NCEs with reduced side effect liabilities have been identified and advanced into clinical evaluation. Glycine is a major inhibitory neurotransmitter in the brain acting via ligand-gated strychnine-sensitive glycine-A receptors. It also acts as a required positive allosteric modulator of glutamate by binding to the glycine-B site on the NMDA receptor, which facilitates glutamate binding to the NMDA complex and enhances excitatory transmission in cortex and hippocampus. Based on the involvement of NMDA receptor-mediated neurotransmission in processes such as cognition, pharmacological manipulation of extracellular synaptic glycine is an active area of research to develop novel treatments for neuropsychiatric disorders. A key component of cerebral glycine metabolism and regulation of synaptic glycine levels is the glycine transporter type 1 (GlyT1). Blockade of GlyT1 to elevate extracellular synaptic glycine concentrations has been hypothesized to potentiate NMDA receptor function in vivo, and represents a rational approach for the treatment of schizophrenia and cognitive disorders. In the next article, Wolkenberg and Sur review the large body of scientific evidence supporting this hypothesis, and the drug discovery efforts to develop potent and selective GlyT1 inhibitors. Metabotropic glutamate receptors (mGluRs) have important roles in synaptic activity in the CNS, and ligands for group I and II mGluRs have been proposed as promising candidates for the treatment of cognitive disorders such as schizophrenia, Fragile X syndrome, Alzheimer's and Parkinson's diseases, and post traumatic stress disorder. The fourth paper in this issue by Andreas Gravius et al. reviews relevant data on the role of specific mGluRs in learning and cognitive processes, focusing on their utility as targets for cognition enhancement in CNS diseases. The 5-HT6 receptor is expressed almost exclusively in the CNS, where blockade of the receptor function increases cholinergic and glutaminergic transmission and in vivo cognitive efficacy in rodent behavior models. Atypical antipsychotics, such as clozapine and olanzapine, bind with high affinity as inverse agonists at 5-HT6 receptors, which coupled with its distribution in key brain areas involved in learning and memory, has enhanced interest in identifying clinical candidates for this target. The review by Rossé and Schaffhauser examines the structure-activity-relationships and the design of novel 5-HT6 receptor ligands and their potential use for the treatment of cognitive impairment. Phosphodiesterases (PDEs) function to hydrolyze the phosphodiester bond and degrade the key second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to control their intracellular levels. The cAMP response element-binding protein (CREB) is a required process in formation of long-term memory and PDE inhibition has been associated with consolidation and retention of LTP in the hippocampus and increased phosphorylation of CREB. PDEs are highly expressed in the CNS and as reviewed by Chris Schmidt, evidence is provided that suggests PDE1B, PDE2, PDE4, PDE5, PDE9 and PDE10 may have therapeutic potential for treating cognitive disorders. I express my sincere gratitude to all the authors that contributed to this special issue of Current Topics in Medicinal Chemistry. My hope is that this issue will serve the cognition field as an informative and ongoing contribution as we all await positive outcomes from the many new approaches in clinical trials.

Nicotinic acetylcholine receptors (nAChR) have been strongly implicated as therapeutic targets for treating cognitive deficits in disorders such as schizophrenia and Alzheimer's disease (AD). In particular α7 and α4β2 subtypeselective nAChR agonists and partial agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Further development of positive allosteric modulators were also recently reported in the literature. In this review we will cover recent developments focused on the above mentioned nAChR subtypes, starting from the most advanced clinical candidate followed by an overview of literature compounds where potency, selectivity, central nervous system access, pharmacological activity and pharmacokinetic properties are disclosed.

The H3 histamine receptor is expressed in many brain regions, including those involved in sleep/wake regulation and cognitive functions. Inhibition of the H3 receptor leads to increased release of multiple neurotransmitters in these regions, making this receptor an ideal target for the potential enhancement of arousal and/or cognitive processes. The high interest level by several pharmaceutical companies in H3 receptors as potential drug targets has produced rapid advancement in novel compound series with different properties, providing a variety of preclinical tools as well as advancing several candidates into clinical trials. Multiple chemotypes have demonstrated efficacy in preclinical models covering a range of cognitive deficits, suggesting the potential value of H3 antagonists as cognition enhancers in a variety of disease states. These studies have revealed the actions of this class of compounds at the cellular, neuronal systems and behavioral levels. Recently, compounds with improved selectivity, pharmacokinetics and preclinical safety profiles have advanced into clinical trials for a number of potential indications. The results of these clinical trials are eagerly awaited and will increase our understanding of the properties of H3 receptor antagonists that will provide therapeutic value.

The simple amino acid glycine is implicated in both inhibitory and excitatory neurotransmission in mammalian central nervous system, and it modulates excitatory neurotransmission through its role as a necessary co-agonist for glutamatergic N-methyl-D-aspartate (NMDA) receptors. Given the involvement of NMDA receptor-mediated neurotransmission in complex cerebral processes such as cognition, pharmacological manipulation of extracellular synaptic glycine biology is an active area of pharmaceutical research to develop novel treatments for neuropsychiatric disorders. A key component of cerebral glycine metabolism is the glycine transporter type 1 (GlyT1) and elevation of extracellular synaptic glycine concentration by blockade of GlyT1 has been hypothesized to potentiate NMDA receptor function in vivo and to represent a rational approach for the treatment of schizophrenia and cognitive disorders. The present article will review the wealth of scientific evidence supporting that hypothesis and the medicinal chemistry effort by many pharmaceutical companies and academic institutions to develop potent and selective GlyT1 inhibitors.

Since more than one decade, metabotropic glutamate receptors have been under investigation as targets for various CNS disorders such as anxiety, pain, depression, schizophrenia, Alzheimer's disease and Parkinson's disease. It has been shown that some mGluRs play a crucial role in cognitive processes such as learning and memory, which was initially, demonstrated using knockout mice for each receptor subtype. Later, selective pharmacological tools were developed allowing more specific examinations of the involvement of mGluR1-8 in various forms of learning and memory. Ligands for group I and II mGluRs have been proposed as promising candidates for the treatment of cognitive disorders such as schizophrenia, Fragile X syndrome, Alzheimer's and Parkinson's disease and posttraumatic stress disorder, of which some have made it to clinical testing. The present paper reviews relevant data on the role of mGluRs in learning and cognition processes focusing on their utility as targets for cognition enhancement in several CNS diseases.

Cognitive impairment (CI) has been recognized as a core feature of Alzheimer's disease (AD) and schizophrenia. The 5-HT6 receptor is an attractive target for the development of cognitive enhancers due to its unique localization and pharmacology. 5-HT6 receptor antagonists have been shown to modulate multiple neurotransmitter systems and therefore enhance cognition in preclinical studies. This premise translated into the clinical efficacy of the 5- HT6 receptor antagonist SB-742457 in mild-to-moderate AD patients. Advances in the understanding of the structureactivity- relationship, the design of novel 5-HT6 receptor ligands and their potential application for the treatment of CI are reviewed.

As might be predicted for an organ designed for cell to cell communication, cyclic nucleotide signaling in the brain is highly organized and regulated. Augmentation of cyclic nucleotide signaling by means of phosphodiesterase inhibition appears to be a viable and tractable means of enhancing neuronal communication. Of the various CNS disorders that have been considered as target indications for phosphodiesterase inhibitors, no condition has received more attention than cognitive dysfunction. This review provides a background for understanding the expanding literature in this field as well as a brief update on the rationale driving the search for selective inhibitors of targets such as PDE1B, PDE2, PDE5 and PDE9.