ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders.
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.
Rueter
Lynne E
LE
Abbott Laboratories, Neuroscience Research, R4N5, AP9A, 100 Abbott Park Rd., Abbott Park, IL 60064-6115, USA. lynne.e.rueter@abbott.com.
Anderson
David J
DJ
Briggs
Clark A
CA
Donnelly-Roberts
Diana L
DL
Gintant
Gary A
GA
Gopalakrishnan
Murali
M
Lin
Nan-Horng
NH
Osinski
Mark A
MA
Reinhart
Glenn A
GA
Buckley
Michael J
MJ
Martin
Ruth L
RL
McDermott
Jeffrey S
JS
Preusser
Lee C
LC
Seifert
Terese R
TR
Su
Zhi
Z
Cox
Bryan F
BF
Decker
Michael W
MW
Sullivan
James P
JP
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy*; D004064:Digestive System / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007858:Learning / Q000187:drug effects*; D051379:Mice; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; C108326:pozanicline