Structure−Activity Studies on 2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine (ABT-089):  An Orally Bioavailable 3-Pyridyl Ether Nicotinic Acetylcholine Receptor Ligand with Cognition-Enhancing Properties

Abstract

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

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

“…In this model, (-)-nicotine disrupts performance at doses as low as 12.4 ìmol/kg (30). In mouse hypothermia studies, ABT-089 does not induce hypothermia at doses up to 62 ìmol/kg as compared to the marked induction of hypothermia seen with (-)-nicotine at 6.2 ìmol/kg (25). Furthermore, in the mouse, ABT-089 is almost 20´less potent at inducing seizures than is (-)-nicotine (ED 50 = 774 ìmol/kg vs. ED 50 = 41 ìmol/kg, respectively; 25).…”

“…In contrast to its equal or greater potency compared to nicotine in cognitive behavioral models, ABT-089 is markedly less potent than nicotine in inducing unwanted behavioral effects. Therefore, whereas (-)-nicotine decreases locomotor activity in mice (ED 50 = 0.62 ìmol/kg) and rats (ED 50 = 1.9 ìmol/kg), ABT-089 does not decrease locomotor activity in doses up to 190 ìmol/kg in either mice or rats (11,25). As stated above, this lack of effect on locomotor activity is also apparent after chronic treatment via minipump (10).…”

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

“…To date, there have been several novel selective a 4 b 2 nAChR agonists developed for the treatment of cognitive deficits associated with schizophrenia and other neurological disorders (see Table 5), including ABT-418, ABT-089, ABT-594, 5-iodo-A-85380, and TC-1734 (AZD3480; isopronicline) (Arneric et al, 1994;Decker et al, 1994b;Lin et al, 1997;Mukhin et al, 2000;Obinu et al, 2002). Preliminary preclinical studies have shown that selective activation of a 4 b 2 improves auditory gating deficits in both DBA/2 mice and in rats (Stevens and Wear, 1997;Wildeboer and Stevens, 2008).…”

Activation of α4β2*/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).…”