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Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science – Editorial Comments
G Model
BCP-12261; No. of Pages 1 Biochemical Pharmacology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Biochemical Pharmacology journal homepage: www.elsevier.com/locate/biochempharm
Editorial
Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science – Editorial Comments Since 2007, Biochemical Pharmacology has published a biennial Special Issue on the nicotinic acetylcholine receptors (nAChRs) as therapeutic targets. These special issues are affiliated with satellite symposia of the annual Society for Neuroscience (SfN) meeting. This year, 2015 will be the 5th Special Issue of Biochemical Pharmacology and the 5th satellite symposium, which will be held on October 14th–15th in Chicago, Illinois. The Symposium and Special Issue will cover the most recent basic and clinical research focused on the development of nAChRs as novel therapeutics. Articles in this special issue cover a wide range of topics related to nAChR structure, function, and pharmacology, including the functional consequences of modulation of their activity in the context of intracellular and circuit signaling. In addition, the participation of the various nAChR subtypes in addiction and disease are discussed, the later including neurodegeneration, e.g. dementia and Parkinson’s disease, inflammatory and immune disorders including myasthenia gravis as well as neuropsychiatric conditions. This wide range of topics is in keeping with the broad participation of cholinergic mechanisms in the peripheral (PNS) and central (CNS) nervous systems as well as in non-neuronal cells. While cholinergic neurotransmission was identified more than a century ago, it is only with the cloning and sequencing of proteins encoding for the receptors that set the direction and pace for the research that ensued. Discovery of the wide distribution of these receptors and their contribution to CNS and PNS function prompted many companies, pharmaceutical and biotech, to develop and characterize compounds selectively targeting these receptors with the aim of treating or correcting neural dysfunction. Numerous efforts, however, have led to limited progress, and only a relatively small number of compounds have reached the advance stages of clinical trials to emerge as potentially efficacious therapies. Designing compounds to treat the CNS is especially difficult, and those difficulties are not specific to the cholinergic system. Rather, related problems of non-specificity and undesired side effects have been encountered with other ligand- and voltagegated ion channels. Despite disorders related to the CNS being the most prevalent category of illness in developed countries, the difficulties and limited success with drug therapies has led to a progressive decline in the research aimed at brain disorders. While most of the large pharmaceutical companies have progressively withdrawn their research forces from this therapeutic area, there is no doubt that brain disorders, including those in which nAChRs play a key role, remain a high priority for society. Technical advances in the field of genetics have led to new approaches to the search for therapies involving the brain, PNS, as
well as non-neuronal targets. The availability of large scale genome-wide scanning marked a step forward in correlating protein modifications with diseases observed in small numbers of individuals. In the nAChR field, such associations have been established between epilepsy or cognitive impairment and the mutations found in CHRNA4 or CHRNB2, the genes encoding for the a4 and b2 subunits of nAChRs. The gene encoding for the a7 nAChR, CHRNA7, has gene duplication or deletion in major cognitive dysfunctions, highlighting its critical function in the human brain. These types of studies provide robust evidence to drive new research initiatives. While the clinical development of selective nAChRs agonists, antagonists and/or modulators has been slow, alternative strategies are under active investigation. Promising results obtained with low doses of a7 agonists in the field of Alzheimer’s disease and schizophrenia have prompted companies to move forward in their clinical trials with Phase-III studies. Moreover, the development of positive (PAMs) or negative (NAMs) allosteric modulators offers additional means by which to selectively modulate cholinergic function selectively. While initial research efforts were mainly on CNS disorders, more recent nAChR research has been directed toward the roles of these receptors in different organ systems and in immune function. Thus, nAChR research is at an exciting time where the convergence of molecular and cellular efforts with behavioral and systems approaches is providing unprecedented opportunities to interpret both animal and human studies. We hope readers will find this Special Issue to be a window on the future therapeutic developments in the nAChR research field. As guest editors, we sincerely thank the stellar collection of experts for their contributions. We also thank Lynn LeCount, Jennifer McNichols, Mike Williams, and the Elsevier staff for their constant support and guidance while bringing this issue to fruition.
John A. Dani Guest Editora,* Diana Donnelly-Roberts Guest Editorb Daniel Bertrand Guest Editorc a Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, Philadelphia, PA 19104, USA b Abbvie Translational Discovery, R4AG/AP52 N1, 1N. Waukegan Rd, North Chicago, IL 60064, USA c HiQ Screen Sa`rl, 6, rte de Compois, 1222 Ve´senaz, Geneva, Switzerland *Corresponding author E-mail address: [email protected] (J.A. Dani). Received 27 April 2015
http://dx.doi.org/10.1016/j.bcp.2015.06.004 0006-2952/ß 2015 Elsevier Inc. All rights reserved.
Please cite this article in press as: Dani JA, et al. Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science – Editorial Comments. Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.06.004
BCP-12261; No. of Pages 1 Biochemical Pharmacology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Biochemical Pharmacology journal homepage: www.elsevier.com/locate/biochempharm
Editorial
Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science – Editorial Comments Since 2007, Biochemical Pharmacology has published a biennial Special Issue on the nicotinic acetylcholine receptors (nAChRs) as therapeutic targets. These special issues are affiliated with satellite symposia of the annual Society for Neuroscience (SfN) meeting. This year, 2015 will be the 5th Special Issue of Biochemical Pharmacology and the 5th satellite symposium, which will be held on October 14th–15th in Chicago, Illinois. The Symposium and Special Issue will cover the most recent basic and clinical research focused on the development of nAChRs as novel therapeutics. Articles in this special issue cover a wide range of topics related to nAChR structure, function, and pharmacology, including the functional consequences of modulation of their activity in the context of intracellular and circuit signaling. In addition, the participation of the various nAChR subtypes in addiction and disease are discussed, the later including neurodegeneration, e.g. dementia and Parkinson’s disease, inflammatory and immune disorders including myasthenia gravis as well as neuropsychiatric conditions. This wide range of topics is in keeping with the broad participation of cholinergic mechanisms in the peripheral (PNS) and central (CNS) nervous systems as well as in non-neuronal cells. While cholinergic neurotransmission was identified more than a century ago, it is only with the cloning and sequencing of proteins encoding for the receptors that set the direction and pace for the research that ensued. Discovery of the wide distribution of these receptors and their contribution to CNS and PNS function prompted many companies, pharmaceutical and biotech, to develop and characterize compounds selectively targeting these receptors with the aim of treating or correcting neural dysfunction. Numerous efforts, however, have led to limited progress, and only a relatively small number of compounds have reached the advance stages of clinical trials to emerge as potentially efficacious therapies. Designing compounds to treat the CNS is especially difficult, and those difficulties are not specific to the cholinergic system. Rather, related problems of non-specificity and undesired side effects have been encountered with other ligand- and voltagegated ion channels. Despite disorders related to the CNS being the most prevalent category of illness in developed countries, the difficulties and limited success with drug therapies has led to a progressive decline in the research aimed at brain disorders. While most of the large pharmaceutical companies have progressively withdrawn their research forces from this therapeutic area, there is no doubt that brain disorders, including those in which nAChRs play a key role, remain a high priority for society. Technical advances in the field of genetics have led to new approaches to the search for therapies involving the brain, PNS, as
well as non-neuronal targets. The availability of large scale genome-wide scanning marked a step forward in correlating protein modifications with diseases observed in small numbers of individuals. In the nAChR field, such associations have been established between epilepsy or cognitive impairment and the mutations found in CHRNA4 or CHRNB2, the genes encoding for the a4 and b2 subunits of nAChRs. The gene encoding for the a7 nAChR, CHRNA7, has gene duplication or deletion in major cognitive dysfunctions, highlighting its critical function in the human brain. These types of studies provide robust evidence to drive new research initiatives. While the clinical development of selective nAChRs agonists, antagonists and/or modulators has been slow, alternative strategies are under active investigation. Promising results obtained with low doses of a7 agonists in the field of Alzheimer’s disease and schizophrenia have prompted companies to move forward in their clinical trials with Phase-III studies. Moreover, the development of positive (PAMs) or negative (NAMs) allosteric modulators offers additional means by which to selectively modulate cholinergic function selectively. While initial research efforts were mainly on CNS disorders, more recent nAChR research has been directed toward the roles of these receptors in different organ systems and in immune function. Thus, nAChR research is at an exciting time where the convergence of molecular and cellular efforts with behavioral and systems approaches is providing unprecedented opportunities to interpret both animal and human studies. We hope readers will find this Special Issue to be a window on the future therapeutic developments in the nAChR research field. As guest editors, we sincerely thank the stellar collection of experts for their contributions. We also thank Lynn LeCount, Jennifer McNichols, Mike Williams, and the Elsevier staff for their constant support and guidance while bringing this issue to fruition.
John A. Dani Guest Editora,* Diana Donnelly-Roberts Guest Editorb Daniel Bertrand Guest Editorc a Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, Philadelphia, PA 19104, USA b Abbvie Translational Discovery, R4AG/AP52 N1, 1N. Waukegan Rd, North Chicago, IL 60064, USA c HiQ Screen Sa`rl, 6, rte de Compois, 1222 Ve´senaz, Geneva, Switzerland *Corresponding author E-mail address: [email protected] (J.A. Dani). Received 27 April 2015
http://dx.doi.org/10.1016/j.bcp.2015.06.004 0006-2952/ß 2015 Elsevier Inc. All rights reserved.
Please cite this article in press as: Dani JA, et al. Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science – Editorial Comments. Biochem Pharmacol (2015), http://dx.doi.org/10.1016/j.bcp.2015.06.004