ABT‐089: Pharmacological Properties of a Neuronal Nicotinic Acetylcholine Receptor Agonist for the Potential Treatment of Cognitive Disorders

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 á 4 â 2 receptor subtype as compared to the á-bungarotoxin (á-BgT) binding sites on the á 7 and á 1 â 1 äã 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 167 CNS Drug Reviews Vol. 10, No. 2, pp. 167-182 © 2004 Neva Press, Branford, Connecticut Address correspondence and reprint requests to Lynne Rueter, Abbott Laboratories, Neuroscience Research, R4N5, AP9A, 100 Abbott Park Rd., Abbott Park, IL 60064-6115, USA. Fax: +1 (847) 938-0072; E-mail: lynne.e.rueter@abbott.com 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.

Activation ofα4β2*/α6β2* Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors

“…ABT-089 [2-methyl-3-[2(S)-pyrrolidinylmethoxy]pyridine; structure in Lin et al, 1997] is a selective partial agonist for a4b2* receptors with high selectivity for a4a5b2 and activity at a6b2* receptors (Rueter et al, 2004;Marks et al, 2009). ABT-089 has been rigorously studied as a treatment of cognitive disorders and has been used successfully in patients with Alzheimer's disease and attention deficit disorder, with few unintended side effects Rueter et al, 2004).…”

Glutamatergic Contributions to Nicotinic Acetylcholine Receptor Agonist-Evoked Cholinergic Transients in the Prefrontal Cortex

“…The cognition enhancer ABT-089 (Decker et al, 1997) was classified as a ␣4␤2*-selective nAChR agonist based on high affinity and selectivity to this receptor subtype (Sullivan et al, 1997). Moreover, partial agonism at this receptor was deduced based on the relatively low efficacy of ABT-089, when compared with nicotine, in stimulating [ 86 Rb ϩ ] efflux from cells expressing human ␣4␤2* nAChRs (Sullivan et al, 1997;Rueter et al, 2004).…”

Pharmacokinetic Modeling and [123I]5-IA-85380 Single Photon Emission Computed Tomography Imaging in Baboons: Optimization of Dosing Regimen for ABT-089

“…Similar to other partial agonists, ABT-089 demonstrated a more advantageous safety profile in preclinical species than full agonists (Rueter et al, 2004), consistent with the notion of an increased safety margin of partial agonists relative to full agonists (Hogg and Bertrand, 2007). However, nicotinic compounds may require high doses to achieve clinical efficacy that, unfortunately, elevates the potential for adverse effects.…”

“…Previous radioligand binding studies have shown that ABT-089 interacts with high affinity at the ␣ 4 ␤ 2 * subtype of both rodent and human nAChRs in which affinities were measured by displacement of specific [ 3 H](Ϫ)-cytisine binding from rat brain membranes (K i ϭ 17 nM) and from human ␣ 4 ␤ 2 * nAChRs stably expressed in a human embryonic kidney cell line (Rueter et al, 2004). Results from our in vivo imaging study show that ABT-089 displaces […”