OBJECTIVES: The aim of this study was to get insight into the central effects of TC-1734 (renamed AZD3480), a selective agonist at the neuronal nicotinic receptor of the alpha4beta2 subtype.

MATERIALS AND METHODS: Electroencephalography (EEG) techniques and computerized cognitive tests were performed in young, healthy male volunteers during two double-blind and placebo-controlled studies: a rising single dose crossover study (from 2 to 320 mg) and a rising repeated dose study with a parallel group design (50, 100, and 200 mg).

RESULTS: In contrast to acute administration, administration of AZD3480 over 10 days produced statistically significant enhancement of several cognitive measures (attention and episodic memory) compared to placebo. Regarding EEG data, AZD3480 showed acceleration of the alpha centroid and of the alpha peak in the single-dose study. This EEG profile of the acceleration type was confirmed in the repeated dose study on both day 1 and day 10, with the greatest effect observed with the highest dose. The EEG pattern shown for AZD3480 was consistent with that previously described with other drugs known to improve attention and vigilance (including nicotine). In addition, subjects dosed with AZD3480 showed a statistically significant increase in mismatch negativity (MMN) amplitude at 50 and 200 mg while reducing MMN latency (200 mg only), suggesting an improvement of pre-attentional mechanisms.

CONCLUSION: These early data in healthy subjects provide encouragement to consider development of AZD3480 as a novel agent for the treatment of cognitive decline in the elderly, including age-associated memory impairment and/or dementia of the Alzheimer's type.