Synthesis and pharmacological characterization of novel analogues of the nicotinic acetylcholine receptor agonist (+/-)-UB-165

C G V Sharples, G Karig, G L Simpson, J A Spencer, E Wright, N S Millar, S Wonnacott, T Gallagher

Research output: Contribution to journalArticle

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Abstract

(+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2*, alpha3beta4, and alpha7). The first class of compounds comprises the three pyridine isomers 4-6, corresponding to the 3-, 2-, and 4-substituted pyridine isomers, respectively. Deschloro UB-165 (4) displayed a 2-3-fold decrease in affinity at alpha4beta2* and alpha3beta4 nAChR subtypes,. as compared with (+/-)-UB- 165, while at the alpha7 subtype a 31-fold increase in affinity was observed. At each of the nAChR subtypes, high affinity binding was dependent on the presence of a 3-substituted pyridine, and the other isomers, 5 and 6, resulted in marked decreases in binding affinities. The second class of compounds is based on replacing the pyridyl unit of 1 with a diazine moiety, giving pyridazine (7), pyrimidine (8), and pyrazine (9), which retain the "3-pyridyl" substructure. Modest reductions in binding affinity were observed for all of the diazine ligands at all nAChR subtypes, with the exception of 7, which retained potency comparable to that of 4 in binding to alpha7 nAChR. In functional assays at the alpha3beta4 nAChR, all analogues 4-9 were less potent, as compared with 1, and the rank order of functional potencies correlated with that of binding potencies. Computational studies indicate that the 3-substituted pyridine 4 and 2-substituted pyridine 5, as well as the diazine analogues 7-9, all conform to a distance-based pharmacophore model recently proposed for the alpha4beta2* receptor. However, the nicotinic potencies of these ligands vary considerably and because 5 lacks appreciable nicotinic activity, it is clear that further refinements of this model are necessary in order to describe adequately the structural and electronic demands associated with this nAChR subtype. This rational series of compounds based on UB-165 presents a systematic approach to defining subtype specific pharmacophores.
Original languageEnglish
Pages (from-to)3235-3245
Number of pages11
JournalJournal of Medicinal Chemistry
Volume45
Issue number15
DOIs
Publication statusPublished - 2002

Fingerprint

Cholinergic Agonists
Nicotinic Receptors
Pharmacology
Ligands
alpha7 Nicotinic Acetylcholine Receptor
Pyrazines
(2-chloro-5-pyridyl)-9-azabicyclo(4.2.1)non-2-ene
pyridine

Cite this

Sharples, C. G. V., Karig, G., Simpson, G. L., Spencer, J. A., Wright, E., Millar, N. S., ... Gallagher, T. (2002). Synthesis and pharmacological characterization of novel analogues of the nicotinic acetylcholine receptor agonist (+/-)-UB-165. Journal of Medicinal Chemistry, 45(15), 3235-3245. https://doi.org/10.1021/jm0208141

Synthesis and pharmacological characterization of novel analogues of the nicotinic acetylcholine receptor agonist (+/-)-UB-165. / Sharples, C G V; Karig, G; Simpson, G L; Spencer, J A; Wright, E; Millar, N S; Wonnacott, S; Gallagher, T.

In: Journal of Medicinal Chemistry, Vol. 45, No. 15, 2002, p. 3235-3245.

Research output: Contribution to journalArticle

Sharples, C G V ; Karig, G ; Simpson, G L ; Spencer, J A ; Wright, E ; Millar, N S ; Wonnacott, S ; Gallagher, T. / Synthesis and pharmacological characterization of novel analogues of the nicotinic acetylcholine receptor agonist (+/-)-UB-165. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 15. pp. 3235-3245.
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AU - Sharples, C G V

AU - Karig, G

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AU - Wright, E

AU - Millar, N S

AU - Wonnacott, S

AU - Gallagher, T

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N2 - (+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2*, alpha3beta4, and alpha7). The first class of compounds comprises the three pyridine isomers 4-6, corresponding to the 3-, 2-, and 4-substituted pyridine isomers, respectively. Deschloro UB-165 (4) displayed a 2-3-fold decrease in affinity at alpha4beta2* and alpha3beta4 nAChR subtypes,. as compared with (+/-)-UB- 165, while at the alpha7 subtype a 31-fold increase in affinity was observed. At each of the nAChR subtypes, high affinity binding was dependent on the presence of a 3-substituted pyridine, and the other isomers, 5 and 6, resulted in marked decreases in binding affinities. The second class of compounds is based on replacing the pyridyl unit of 1 with a diazine moiety, giving pyridazine (7), pyrimidine (8), and pyrazine (9), which retain the "3-pyridyl" substructure. Modest reductions in binding affinity were observed for all of the diazine ligands at all nAChR subtypes, with the exception of 7, which retained potency comparable to that of 4 in binding to alpha7 nAChR. In functional assays at the alpha3beta4 nAChR, all analogues 4-9 were less potent, as compared with 1, and the rank order of functional potencies correlated with that of binding potencies. Computational studies indicate that the 3-substituted pyridine 4 and 2-substituted pyridine 5, as well as the diazine analogues 7-9, all conform to a distance-based pharmacophore model recently proposed for the alpha4beta2* receptor. However, the nicotinic potencies of these ligands vary considerably and because 5 lacks appreciable nicotinic activity, it is clear that further refinements of this model are necessary in order to describe adequately the structural and electronic demands associated with this nAChR subtype. This rational series of compounds based on UB-165 presents a systematic approach to defining subtype specific pharmacophores.

AB - (+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2*, alpha3beta4, and alpha7). The first class of compounds comprises the three pyridine isomers 4-6, corresponding to the 3-, 2-, and 4-substituted pyridine isomers, respectively. Deschloro UB-165 (4) displayed a 2-3-fold decrease in affinity at alpha4beta2* and alpha3beta4 nAChR subtypes,. as compared with (+/-)-UB- 165, while at the alpha7 subtype a 31-fold increase in affinity was observed. At each of the nAChR subtypes, high affinity binding was dependent on the presence of a 3-substituted pyridine, and the other isomers, 5 and 6, resulted in marked decreases in binding affinities. The second class of compounds is based on replacing the pyridyl unit of 1 with a diazine moiety, giving pyridazine (7), pyrimidine (8), and pyrazine (9), which retain the "3-pyridyl" substructure. Modest reductions in binding affinity were observed for all of the diazine ligands at all nAChR subtypes, with the exception of 7, which retained potency comparable to that of 4 in binding to alpha7 nAChR. In functional assays at the alpha3beta4 nAChR, all analogues 4-9 were less potent, as compared with 1, and the rank order of functional potencies correlated with that of binding potencies. Computational studies indicate that the 3-substituted pyridine 4 and 2-substituted pyridine 5, as well as the diazine analogues 7-9, all conform to a distance-based pharmacophore model recently proposed for the alpha4beta2* receptor. However, the nicotinic potencies of these ligands vary considerably and because 5 lacks appreciable nicotinic activity, it is clear that further refinements of this model are necessary in order to describe adequately the structural and electronic demands associated with this nAChR subtype. This rational series of compounds based on UB-165 presents a systematic approach to defining subtype specific pharmacophores.

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