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PMID: 15179445 Published · ppublish English Journal Article Review

ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders.

CNS drug reviews ·Vol. 10 ·No. 2 ·2004-00-00 ·Pages 167-82

Rueter LE, Anderson DJ, Briggs CA, Donnelly-Roberts DL, Gintant GA, Gopalakrishnan M, Lin NH, Osinski MA, Reinhart GA, Buckley MJ, Martin RL, McDermott JS, Preusser LC, Seifert TR, Su Z, Cox BF, Decker MW, Sullivan JP

Abstract

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the alpha4beta2 receptor subtype as compared to the alpha-bungarotoxin (alpha-BgT) binding sites on the alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT-089 is as potent and efficacious as (-)-nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT-089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT-089 shows little propensity to induce adverse effects such as ataxia, hypothermia, seizures, cardiovascular or gastrointestinal side effects. Together these data suggest that ABT-089 is a NNR modulator with the potential for treating cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects.

MeSH Terms
Animals Cardiovascular System/drug effects Cognition Disorders/drug therapy Digestive System/drug effects Dogs Dose-Response Relationship, Drug Humans Learning/drug effects Mice Nicotinic Agonists/chemistry,pharmacology,therapeutic use Pyridines/chemistry,pharmacology,therapeutic use Pyrrolidines/chemistry,pharmacology,therapeutic use Rats
Chemicals
Nicotinic Agonists Pyridines Pyrrolidines pozanicline
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Rueter Lynne E
Abbott Laboratories, Neuroscience Research, R4N5, AP9A, 100 Abbott Park Rd., Abbott Park, IL 60064-6115, USA. [email protected].
Anderson David J
Briggs Clark A
Donnelly-Roberts Diana L
Gintant Gary A
Gopalakrishnan Murali
Lin Nan-Horng
Osinski Mark A
Reinhart Glenn A
Buckley Michael J
Martin Ruth L
McDermott Jeffrey S
Preusser Lee C
Seifert Terese R
Su Zhi
Cox Bryan F
Decker Michael W
Sullivan James P
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Article Info
Journal
CNS drug reviews
Abbr.
CNS Drug Rev
ISSN
1080-563X
DOI
10.1111/j.1527-3458.2004.tb00011.x
Email
[email protected]
Published
2004-00-00
Pages
167-82
Language
English
Region
United States
NLM ID
9514898
PMCID
PMC6741767
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1527-3458.2004.tb00011.x PMC Full Text
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