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Nicotine activates specific receptors that are cation-permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC-1827, a novel metanicotine derivative that activates brain a 4 b 2 nicotinic receptors is described. TC-1827 has high affinity for nicotine-labeled receptors in the cortex (K i ¼ 34 nM), full-agonist intrinsic activity in a 4 b 2 -mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long-term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC-1827 dose-dependently occupies thalamic nicotinic receptors labeled with [ 3 H]-cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC-1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13-65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC-1827 is a selective and potent activator of brain a 4 b 2 nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev.