AZD1446 (TC-6683), a novel alpha4beta2 nAChR agonist with cognitive-enhancing properties (Neuroscience 2012) - Aug 20, 2012 - Presentation time: Tuesday, Oct 16, 2012, 10:00 AM -11:00 AM; AZD1446 reverseed cognitive deficits produced by scopolamine and dizocilpine in RAM and WM models and improves attentional performance in normal animals and reverses impairments (10mg/kg) in dizoclipine-treated animals; Cognitive enhancing properties are long-lasting (18h in NOR and 24h in RAM) and sustained following repeated dosing
Preclinical-animal • Alzheimer's Disease
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Neuroscience, Oct 13-17, 2012
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532.15/B42
Worldwide, nearly 36 million people are believed to be afflicted with Alzheimer's disease (AD) or dementia. That number is projected to increase to 65.7 million by 2030 and 115.4 million by 2050. Current treatments for AD remain inadequate due to the transient clinical efficacy these drugs provide in the symptomatic treatment of memory loss. The major driver for improved therapy in AD is the need for superior symptomatic treatment. Of the potential treatments currently in development, the nicotinic agonist approach has shown promise in the clinical. AZD1446 (TC-6683) is an agonist of the α4β2 subtype of nicotinic acetylcholine receptor (nAChR) with marked CNS selectivity. This compound binds with high affinity to rat brain nicotinic receptors with a Ki of 34 nM and activates functional responses (Ca++ flux and dopamine release) in the range of 2-4 µM. AZD1446 displays comparatively low selectivity for peripheral (muscular and ganglionic) and α7 central nAChRs. The lack of interaction with muscle and ganglion-type receptors as well as the good selectivity in a large binding profile, suggest a reduced potential for side effects. AZD1446 is active orally in three different cognitive tests (novel object recognition (NOR), radial arm maze (RAM) and water maze (WM) with a broad dose-response effect and a therapeutic oral dose in the range of 0.03-3 mg/kg. In addition, AZD1446 is able to reverse cognitive deficits produced by scopolamine and dizocilpine in the RAM and WM models. AZD1446 (0.1 mg/kg) improves attentional performance in normal animals and reverses impairments (10 mg/kg) in dizoclipine-treated animals. The cognitive enhancing properties of this compound are long-lasting (18h in NOR and 24h in RAM) and sustained following repeated dosing. When compared to donepezil, AZD1446 demonstrates superior cognitive enhancing properties in aged animals. The ability to improve cognition following oral administration makes this compound an excellent candidate for further evaluation to treat the cognitive deficits observed in Alzheimer’s disease.
(IR2)
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