oa Editorial [Hot topic: Current Approaches for the Treatment of Cognitive Deficits in CNS Disease (Guest Editor: Robert L. Hudkins)]

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.