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In vitro and in vivo characterization of TC-1827, a novel brain α4β2 nicotinic receptor agonist with pro-cognitive activity
Drug development research, 2004-05, Vol.62 (1), p.26-40
Bohme, Georg Andrees
Letchworth, Sharon R.
Piot-Grosjean, Odile
Gatto, Gregory J.
Obinu, Marie-Carmen
Caldwell, William S.
Laville, Michel
Brunel, Pascale
Pellerin, Rachel
Leconte, Jean-Pierre
Genevois-Borella, Arielle
Dubedat, Pierre
Mazadier, Martine
Pradier, Laurent
Bencherif, Merouane
Benavides, Jesus
2004
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Autor(en) / Beteiligte
Bohme, Georg Andrees
Letchworth, Sharon R.
Piot-Grosjean, Odile
Gatto, Gregory J.
Obinu, Marie-Carmen
Caldwell, William S.
Laville, Michel
Brunel, Pascale
Pellerin, Rachel
Leconte, Jean-Pierre
Genevois-Borella, Arielle
Dubedat, Pierre
Mazadier, Martine
Pradier, Laurent
Bencherif, Merouane
Benavides, Jesus
Titel
In vitro and in vivo characterization of TC-1827, a novel brain α4β2 nicotinic receptor agonist with pro-cognitive activity
Ist Teil von
Drug development research, 2004-05, Vol.62 (1), p.26-40
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2004
Quelle
Wiley-Blackwell Journals
Beschreibungen/Notizen
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 α4β2 nicotinic receptors is described. TC‐1827 has high affinity for nicotine‐labeled receptors in the cortex (Ki=34 nM), full‐agonist intrinsic activity in α4β2‐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 [3H]‐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 α4β2 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. Res. 62:26–40, 2004. © 2004 Wiley‐Liss, Inc.
Sprache
Englisch
Identifikatoren
ISSN: 0272-4391
eISSN: 1098-2299
DOI: 10.1002/ddr.10352
Titel-ID: cdi_pascalfrancis_primary_16225561
Format
–
Schlagworte
acetylcholine receptors
,
Alzheimer's disease
,
Biological and medical sciences
,
Cholinergic system
,
ion flux
,
learning and memory
,
long-term potentiation
,
Medical sciences
,
Neuropharmacology
,
neurotransmitter release
,
Neurotransmitters. Neurotransmission. Receptors
,
Pharmacology. Drug treatments
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