Abbott Researchers Target Neuronal Nicotinic Receptors for Treatment of Pain and Cognition
Scientists to Present Data and Discuss Emerging Advances in Basic Research and Clinical Science at Neuroscience 2007 Satellite Symposium
The human brain relies on chemicals called “neurotransmitters” that nerve cells use to communicate to one another, in order to maintain a wide range of cognitive functions including memory and attention. Based on a growing body of scientific knowledge related to neurotransmitters, the scientific community is now targeting neuronal nicotinic receptors (NNRs), found on nerve cells throughout the central nervous system, to treat a number of psychiatric and neurological disorders. NNRs, also known as neuronal nicotinic acetylcholine receptors (nAChRs), modulate the release of several important neurotransmitters, such as acetylcholine and dopamine.
Abbott researchers are currently developing selective NNR compounds, which act as agonists (drugs that stimulate activity at cell receptors) at specific NNR sites in the body, for attention-deficit hyperactivity disorder, Alzheimer’s disease, schizophrenia and pain – conditions for which there are still significant unmet needs in spite of available treatment options. Scientists from independent academic institutions and Abbott will present data on these compounds at the Neuroscience 2007 satellite symposium entitled “Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science.” The meeting takes place Oct. 31 to Nov. 2 at the San Diego Convention Center, preceding the annual meeting of the Society for Neuroscience.
Presentations highlighting Abbott compounds include the following:
Integrative Pharmacology of nAChRs and nAChR Ligands
Bryan F. Cox, Abbott(Thursday, Nov. 1, 8 a.m.)
Preclinical and Clinical Studies with Novel nAChR Ligands in Pain
Michael D. Meyer, Abbott(Thursday, Nov. 1, 2:10 p.m.)
ADHD Overview, Preclinical nAChR Pharmacology
Michael W. Decker, Abbott (Friday, Nov. 2, 10 a.m.)
Clinical Studies with nAChR Ligands in ADHD
Timothy E. Wilens, Harvard Medical School(Friday, Nov. 2, 10 a.m.)
“While many advances have been made in the treatment of neurobehavioral disorders, considerable unmet medical need still exists,” said Timothy Wilens, M.D., associate professor of Psychiatry, Harvard Medical School. “NNR agonist compounds have the tremendous potential of improving the core and associated symptoms of attention-deficit hyperactivity disorder without apparently producing cardiovascular effects and other more common side effects such as insomnia and appetite suppression observed with current treatments.”
“Preclinical and clinical data support the potential of NNR agonists to alleviate the cognitive deficits associated with a variety of disorders, as well as pain,” said James Sullivan, Ph.D., divisional vice president, Neuroscience Discovery, Abbott. “Abbott has significant experience in this area and has been among the leaders in advancing the understanding of the therapeutic potential of NNRs for more than a decade. Our scientists have been at the forefront of identifying selective NNR agonists and have published more than 75 research studies in this area.”
Building on the company’s strong scientific foundation in neuroscience and pain, Abbott has significant research and development efforts underway to investigate new therapeutic approaches to cognitive disorders, such as attention-deficit hyperactivity disorder, Alzheimer’s disease and schizophrenia. Abbott also is investigating new therapies for nociceptive pain conditions such as osteoarthritis and cancer pain, as well as neuropathic pain conditions such as diabetic neuropathy.
The following investigational programs are examples of Abbott’s broad portfolio of neuroscience and pain care research. These programs include and extend beyond NNR therapeutics:
α4β2 NNR Agonist Program
ABT-089 is a partial and selective NNR agonist, which targets the α4β2 NNR subtype. It has demonstrated efficacy in preclinical models of attention, learning and memory deficits. It also has demonstrated efficacy in improving the core symptoms of attention-deficit hyperactivity disorder in adults. ABT-089 is currently in Phase II clinical trials for adult attention-deficit hyperactivity disorder and is being studied for other cognitive diseases.
ABT-894 is an NNR agonist, which targets the α4β2 NNR subtype. It has demonstrated efficacy in multiple preclinical animal models of neuropathic pain and nociceptive pain with and without an inflammatory component. ABT-894 exhibits high affinity for and full functional efficacy at the α4β2 NNR subtype. Similar to other NNR agonists, it also has demonstrated a cognitive enhancing profile in pre-clinical models of cognition. ABT-894 is currently in Phase II clinical trials for adult attention-deficit hyperactivity disorder and diabetic neuropathic pain. This compound was discovered in collaboration with NeuroSearch.
α7 NNR Agonist Program
ABT-107 promises to be a potent and selective NNR agonist, which targets the α7 NNR subtype. It has demonstrated efficacy in in vivo studies that model memory consolidation, social recognition memory, working memory, and sensory gating deficits, which are domains of cognition negatively impacted in Alzheimer’s disease and schizophrenia. ABT-107 is currently in Phase I clinical trials for a variety of central nervous system disorders. This compound was discovered in collaboration with NeuroSearch.
D3 Receptor Antagonist Program
In addition to the focus on NNR research, Abbott has an aggressive pre-clinical and clinical program evaluating selective D3 receptor antagonists. D3 receptors are expressed in brain regions associated with schizophrenia, and most current antipsychotics bind to D3 receptors. However, current antipsychotic medications are non-selective for the D3 receptors and have little effect on negative symptoms (i.e., apathy, lack of emotion, poor or nonexistent social functioning) or on cognitive deficits (i.e., disorganized thoughts, difficulty concentrating and/or following instructions, difficulty completing tasks, memory problems).
Abbott’s pre-clinical, selective D3 compounds show high potency and selectivity for D3 receptors and have demonstrated efficacy in a number of preclinical models assessing antipsychotic efficacy. In preclinical studies, they do not induce secondary negative symptoms, extrapyramidal side effects (physical symptoms that can occur in individuals taking antipsychotic medications) or neuroendocrine disturbances associated with current agents.
ABT-925 promises to be a potent and selective dopamine D3 receptor antagonist, currently in early Phase II clinical trials for schizophrenia. The pharmacological profile of ABT-925 suggests that it will be differentiated from current antipsychotic agents by a broad range of therapeutic efficacy and diminished on-target and off-target (e.g. D2, H1 and α1 adrenoceptor) side effects.
TRPV1 Receptor Program
The TRPV1, or vanilloid receptor, plays an important role in mediating the body’s response to a variety of pain stimuli, including heat and changes in pH levels, as well as a variety of mediators of inflammation that are released in the body following tissue damage. Abbott has identified a number of compounds that may have the ability to elicit relief across a broad spectrum of pain states. The lead compounds have demonstrated efficacy comparable to morphine across a number of different pre-clinical pain models – including osteoarthritis, post-operative and cancer pain.
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