ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties.
Accumulating preclinical and clinical evidence data suggests that compounds that selectively activate neuronal nicotinic acetylcholine receptor (nAChR) subtypes may have therapeutic utility for the treatment of several neurological disorders. In the present study, the in vitro pharmacological properties of the novel cholinergic channel modulator ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine], are described. In radioligand binding studies, ABT-089 was shown to display selectivity toward the high-affinity (-)-cytisine binding site present on the alpha4beta2 nAChR subtype (Ki = 16 nM) relative to the [125I]alpha-bungarotoxin binding site present on the alpha7 (Ki > or = 10,000 nM) and alpha1beta1deltagamma (Ki > 1000 nM) nAChR subtypes. In cation flux and channel current studies, ABT-089 displayed a more complex profile than (-)-nicotine having agonist, partial agonist and inhibitory activities depending on the nAChR subtype with which it interacts. ABT-089 differentially stimulated neurotransmitter release. The compound displayed a similar potency and efficacy to (-)-nicotine to facilitate ACh release (ABT-089, EC50 = 3 microM; (-)-nicotine, EC50 = 1 microM), but was markedly less potent and less efficacious than (-)-nicotine to stimulate dopamine release (ABT-089, EC50 = 1.1 microM; (-)-nicotine, EC50 = 0.04 microM). Additionally, ABT-089 was neuroprotective against the excitotoxic insults elicited by exposure to glutamate in both rat cortical cell cultures (EC50 = 10 +/- 3 microM) and differentiated human IMR32 cells (EC50 = 3 +/- 2 microM). The differential full agonist/partial agonist profile of ABT-089, as compared with (-)-nicotine and ABT-418, illustrates the complexity of nAChR activation and the potential to target responses at subclasses of the neuronal and peripheral receptors.
Sullivan
J P
JP
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Donnelly-Roberts
D
D
Briggs
C A
CA
Anderson
D J
DJ
Gopalakrishnan
M
M
Xue
I C
IC
Piattoni-Kaplan
M
M
Molinari
E
E
Campbell
J E
JE
McKenna
D G
DG
Gunn
D E
DE
Lin
N H
NH
Ryther
K B
KB
He
Y
Y
Holladay
M W
MW
Wonnacott
S
S
Williams
M
M
Arneric
S P
SP
D000109:Acetylcholine / Q000378:metabolism; D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D001392:Azocines; D018678:Cholinergic Agents / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011807:Quinolizines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012414:Rubidium Radioisotopes / Q000378:metabolism; D014982:Xenopus laevis; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D001392:Azocines; D018678:Cholinergic Agents; D004298:Dopamine; D007473:Ion Channels; D018696:Neuroprotective Agents; D011725:Pyridines; D011759:Pyrrolidines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C108326:pozanicline