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

Nan Horng Lin; David E. Gunn; Keith B. Ryther; David S. Garvey; Diana L. Donnelly-Roberts; Michael W. Decker; Jorge D. Brioni; Michael J. Buckley; A. David Rodrigues; Kennan G. Marsh; David J. Anderson; Jerry J. Buccafusco; Mark A. Prendergast; James P. Sullivan; Michael Williams; Stephen P. Arneric; Mark W. Holladay

doi:10.1021/jm960233u

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

Nan Horng Lin, David E. Gunn, Keith B. Ryther, David S. Garvey, Diana L. Donnelly-Roberts, Michael W. Decker, Jorge D. Brioni, Michael J. Buckley, A. David Rodrigues, Kennan G. Marsh, David J. Anderson, Jerry J. Buccafusco, Mark A. Prendergast, James P. Sullivan, Michael Williams, Stephen P. Arneric, Mark W. Holladay

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70 Scopus citations

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.

Original language	English
Pages (from-to)	385-390
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	40
Issue number	3
DOIs	https://doi.org/10.1021/jm960233u
State	Published - Jan 31 1997

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Lin, N. H., Gunn, D. E., Ryther, K. B., Garvey, D. S., Donnelly-Roberts, D. L., Decker, M. W., Brioni, J. D., Buckley, M. J., Rodrigues, A. D., Marsh, K. G., Anderson, D. J., Buccafusco, J. J., Prendergast, M. A., Sullivan, J. P., Williams, M., Arneric, S. P., & Holladay, M. W. (1997). 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. Journal of Medicinal Chemistry, 40(3), 385-390. https://doi.org/10.1021/jm960233u

@article{2520f3ce00cd4d65baadfdf3425a62ab,

title = "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.",

author = "Lin, {Nan Horng} and Gunn, {David E.} and Ryther, {Keith B.} and Garvey, {David S.} and Donnelly-Roberts, {Diana L.} and Decker, {Michael W.} and Brioni, {Jorge D.} and Buckley, {Michael J.} and Rodrigues, {A. David} and Marsh, {Kennan G.} and Anderson, {David J.} and Buccafusco, {Jerry J.} and Prendergast, {Mark A.} and Sullivan, {James P.} and Michael Williams and Arneric, {Stephen P.} and Holladay, {Mark W.}",

year = "1997",

month = jan,

day = "31",

doi = "10.1021/jm960233u",

language = "English",

volume = "40",

pages = "385--390",

number = "3",

}

Lin, NH, Gunn, DE, Ryther, KB, Garvey, DS, Donnelly-Roberts, DL, Decker, MW, Brioni, JD, Buckley, MJ, Rodrigues, AD, Marsh, KG, Anderson, DJ, Buccafusco, JJ, Prendergast, MA, Sullivan, JP, Williams, M, Arneric, SP & Holladay, MW 1997, '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', Journal of Medicinal Chemistry, vol. 40, no. 3, pp. 385-390. https://doi.org/10.1021/jm960233u

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. / Lin, Nan Horng; Gunn, David E.; Ryther, Keith B. et al.
In: Journal of Medicinal Chemistry, Vol. 40, No. 3, 31.01.1997, p. 385-390.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Structure-activity studies on 2-methyl-3-(2(S)- pyrrolidinylmethoxy)pyridine (ABT-089)

T2 - An orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties

AU - Lin, Nan Horng

AU - Gunn, David E.

AU - Ryther, Keith B.

AU - Garvey, David S.

AU - Donnelly-Roberts, Diana L.

AU - Decker, Michael W.

AU - Brioni, Jorge D.

AU - Buckley, Michael J.

AU - Rodrigues, A. David

AU - Marsh, Kennan G.

AU - Anderson, David J.

AU - Buccafusco, Jerry J.

AU - Prendergast, Mark A.

AU - Sullivan, James P.

AU - Williams, Michael

AU - Arneric, Stephen P.

AU - Holladay, Mark W.

PY - 1997/1/31

Y1 - 1997/1/31

N2 - 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.

AB - 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.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 3

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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

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