Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys
Introduction
Central nicotinic acetylcholine receptors (nAChRs) serve as potential therapeutic targets for a wide number of human diseases [1], [2], [3], [4]. For example, nicotine and a number of nAChR agonists have been evaluated as potential cognition-enhancing agents, particularly for the treatment of Alzheimer's disease [1], [4], [5], [6], [7], [8], [9], [10]. Our laboratory has had the opportunity to study a wide variety of compounds targeting nicotinic receptors for cognition enhancement in non-human primates. These compounds produce varying degrees of improvement in delayed matching-to-sample (DMTS) task accuracies in both young adult and aged (>19-year-old) macaques [4], [6], [11]. Nicotine and the synthetic nicotinic agonists ABT-418, ABT-089, and SIB-1553A were shown to improve accuracies by monkeys performing the standard DMTS task [12], [13], [14]; but they were also effective in a version of the DMTS task that measures attention, i.e., in which non-predictable distractors are inserted within the DMTS format [15], [16].
Some of these early nAChR ligands were not sufficiently subtype-selective to avoid some of the more common nicotinic side effects. The synthesis and characterization of novel synthetic nAChR agonists binding selectively to either the hetero-oligomeric α4β2 or to the homo-oligomeric α7 nAChR subtype has uncovered the specific pharmacological responses mediated by the two subtypes. One of the most studied compounds, both preclinically and clinically, largely for its potential as an analgesic agent [17], is ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) (ABT-594) [18]. ABT-594 displays high affinity in displacing [3H](−)-cytisine from α4β2 neuronal nAChRs (Ki = 37–55 pM), and has greater than 180,000-fold selectivity for the α4β2 subtype relative to the α1β1δγ neuromuscular nicotinic receptor labeled by [125I]α-bungarotoxin [19]. ABT-594 is approximately 25 times more potent than nicotine in displacing [3H](−)-cytisine binding to α4β2 receptors; but exhibits three-fold less affinity relative to nicotine binding α7 homo-oligomeric nicotinic receptors (estimated by displacement of [125I]α-bungarotoxin binding). Though epibatidine is 60-fold more potent than ABT-594 in α7 binding assays, the compounds are equipotent with respect to α4β2 receptors. Thus, ABT-594 is significantly more selective for α4β2 receptors in binding studies than either nicotine or epibatidine. With respect to functional studies, ABT-594 is about 17 times more potent than nicotine at human α4β2 (and more efficacious than nicotine) in the ability to enhance calcium flux in a stable cell line, but the analog is only about 1.5 times more potent than nicotine at human α7 receptors (with the same efficacy) as measured electrophysiologically in transfected oocytes. Thus, for ABT-594 the available evidence indicates a net improvement over nicotine selectivity with respect to the α4β2 and α7 subtypes by a factor of 75 in binding studies and slightly more than a factor of 10 in functional studies [18]. In a related in vivo study ABT-594 treatment in rats was shown to increase the brain expression of fibroblast growth factor-2 mRNA [20]. Consistent with its in vitro binding profile, these effects of ABT-594 were antagonized by the partly α4β2-selective nicotinic receptor antagonist dihydro-β-erythroidine, but not by the selective α7 antagonist methyllycaconitine.
The α7 homo-oligomeric subtype of nAChRs is not as highly expressed as the α4β2 subtype, but compounds targeting α7 receptors also have been developed for therapeutic potential [4], [21], [22], [23]. Agonists for α7 receptors have been reported to produce neuroprotective activity [24], [25], [26], [27] and to enhance cognition in a variety of experimental models [28], [29], [30]. A preliminary report regarding the pharmacological characterization of A-582491 (2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole) indicated significant α7 subtype selectivity. The compound also stimulated MAPK/ERK1/2/CREB phosphorylation in PC12 cells, a CNS signaling pathway involved in learning and memory consolidation, and increased ERK1/2 and CREB phosphorylation in mouse cingulate cortex and hippocampus. Unlike some of the initially disclosed quinuclidine-derived α7 agonists, A-582941 exhibited excellent CNS penetration at least in rodents [31].
The purpose of this study was to compare the abilities of ABT-594 and A-582941 to improve accuracies by monkeys in their performance of the DMTS task. The expectation was that differences between the pharmacological responses evoked by the two compounds might reflect their relative selectivities for the two major nAChR subtypes.
Section snippets
Study subjects
All procedures were reviewed and approved by the Medical College of Georgia Institutional Animal Care and Use Committee and they are consistent with AAALAC guidelines. The subjects used in this study (Table 1), seven adult male Rhesus monkeys (Macaca mulatta) were individually housed at the Animal Behavior Center of the Medical College of Georgia in stainless steel cages composed of multiple 127 cm × 71 cm × 66 cm units. To promote psychological well-being toys and foraging tubes were provided
Standard DMTS testing
For this experimental series, part of the dose–response relationship was obtained on two separate occasions in the same subjects (the two highest doses were examined only one time). The data for duplicate doses were combined in the analysis. During the course of this study standard DMTS vehicle sessions were performed on eight occasions (four for each dose–response relationship). These values were averaged to provide the vehicle baseline means against which all subsequent drug sessions were
Discussion
In the present study ABT-594 was shown to produce a significant improvement in standard DMTS task accuracy. A discussion of the mnemonic properties of ABT-594 might be developed from a comparison with the known effects of nicotine and other nicotinic receptor agonists studied under similar circumstances. For example, in young macaques, nicotine and the analogs ABT-418 and ABT-089 each improved DMTS task accuracy with similar potency and efficacy [13], [34]. ABT-594 proved to be the most potent
Acknowledgements
This work was supported by Abbott Labs, Abbott Park, Illinois, and by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The authors would like to thank Ms. Nancy Kille for her excellent technical assistance in working with primate subjects.
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- 1
The author was a collaborator who studied these compounds in the monkey DMTS task.
- 2
The author is an employee of Abbott Labs.