Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes

Y. E. Slater, L. M. Houlihan, P. D. Maskell, R. Exley, I. Bermúdez, R. J. Lukas, A. C. Valdivia, B. K. Cassels*

*Corresponding author for this work

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Cytisine (cy) is a potent and competitive partial agonist at α4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric α7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine (N-Me-cy) on the effects of these compounds on recombinant human (h) α7, hα4β2 and hα4β4 nACh receptors expressed in clonal cell lines and Xenopus oocytes. Halogenation at C(3) of cy or N-Me-cy usually brings about a marked increase in both affinity and efficacy at hα7, hα4β2 and hα4β4 nACh, the extent of which depends on whether the halogen is bromine or iodine, and upon receptor subtype. The effects of halogenation at C(5) are strongly influenced by the specific halogen substituent so that bromination causes a decrease in both affinity and efficacy while iodination decreases affinity but its effects on efficacy range from a decrease (hα7, hα4β4 nACh receptors) to a marked increase (hα4β2 nACh receptors). Based on these findings, which differ from those showing that neither the affinity nor efficacy of nicotine, 3-(2-azetidinylmethoxy)-pyridine or epibatidine are greatly affected by halogenation, dehalogenation or halogen exchange at equivalent positions, we suggest that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobic agonist-binding pocket of the receptors.

Original languageEnglish
Pages (from-to)503-515
Number of pages13
JournalNeuropharmacology
Volume44
Issue number4
Early online date22 Feb 2003
DOIs
Publication statusPublished - Mar 2003
Externally publishedYes

Fingerprint

Halogenation
Nicotinic Receptors
Halogens
epibatidine
A 85380
Pyridones
Bromine
Xenopus
cytisine
Nicotine
Iodine
Acetylcholine
Oocytes
Cell Line

Cite this

Slater, Y. E. ; Houlihan, L. M. ; Maskell, P. D. ; Exley, R. ; Bermúdez, I. ; Lukas, R. J. ; Valdivia, A. C. ; Cassels, B. K. / Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes. In: Neuropharmacology. 2003 ; Vol. 44, No. 4. pp. 503-515.
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title = "Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes",
abstract = "Cytisine (cy) is a potent and competitive partial agonist at α4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric α7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine (N-Me-cy) on the effects of these compounds on recombinant human (h) α7, hα4β2 and hα4β4 nACh receptors expressed in clonal cell lines and Xenopus oocytes. Halogenation at C(3) of cy or N-Me-cy usually brings about a marked increase in both affinity and efficacy at hα7, hα4β2 and hα4β4 nACh, the extent of which depends on whether the halogen is bromine or iodine, and upon receptor subtype. The effects of halogenation at C(5) are strongly influenced by the specific halogen substituent so that bromination causes a decrease in both affinity and efficacy while iodination decreases affinity but its effects on efficacy range from a decrease (hα7, hα4β4 nACh receptors) to a marked increase (hα4β2 nACh receptors). Based on these findings, which differ from those showing that neither the affinity nor efficacy of nicotine, 3-(2-azetidinylmethoxy)-pyridine or epibatidine are greatly affected by halogenation, dehalogenation or halogen exchange at equivalent positions, we suggest that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobic agonist-binding pocket of the receptors.",
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Slater, YE, Houlihan, LM, Maskell, PD, Exley, R, Bermúdez, I, Lukas, RJ, Valdivia, AC & Cassels, BK 2003, 'Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes', Neuropharmacology, vol. 44, no. 4, pp. 503-515. https://doi.org/10.1016/S0028-3908(03)00025-X

Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes. / Slater, Y. E.; Houlihan, L. M.; Maskell, P. D.; Exley, R.; Bermúdez, I.; Lukas, R. J.; Valdivia, A. C.; Cassels, B. K.

In: Neuropharmacology, Vol. 44, No. 4, 03.2003, p. 503-515.

Research output: Contribution to journalArticle

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T1 - Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes

AU - Slater, Y. E.

AU - Houlihan, L. M.

AU - Maskell, P. D.

AU - Exley, R.

AU - Bermúdez, I.

AU - Lukas, R. J.

AU - Valdivia, A. C.

AU - Cassels, B. K.

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N2 - Cytisine (cy) is a potent and competitive partial agonist at α4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric α7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine (N-Me-cy) on the effects of these compounds on recombinant human (h) α7, hα4β2 and hα4β4 nACh receptors expressed in clonal cell lines and Xenopus oocytes. Halogenation at C(3) of cy or N-Me-cy usually brings about a marked increase in both affinity and efficacy at hα7, hα4β2 and hα4β4 nACh, the extent of which depends on whether the halogen is bromine or iodine, and upon receptor subtype. The effects of halogenation at C(5) are strongly influenced by the specific halogen substituent so that bromination causes a decrease in both affinity and efficacy while iodination decreases affinity but its effects on efficacy range from a decrease (hα7, hα4β4 nACh receptors) to a marked increase (hα4β2 nACh receptors). Based on these findings, which differ from those showing that neither the affinity nor efficacy of nicotine, 3-(2-azetidinylmethoxy)-pyridine or epibatidine are greatly affected by halogenation, dehalogenation or halogen exchange at equivalent positions, we suggest that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobic agonist-binding pocket of the receptors.

AB - Cytisine (cy) is a potent and competitive partial agonist at α4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric α7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine (N-Me-cy) on the effects of these compounds on recombinant human (h) α7, hα4β2 and hα4β4 nACh receptors expressed in clonal cell lines and Xenopus oocytes. Halogenation at C(3) of cy or N-Me-cy usually brings about a marked increase in both affinity and efficacy at hα7, hα4β2 and hα4β4 nACh, the extent of which depends on whether the halogen is bromine or iodine, and upon receptor subtype. The effects of halogenation at C(5) are strongly influenced by the specific halogen substituent so that bromination causes a decrease in both affinity and efficacy while iodination decreases affinity but its effects on efficacy range from a decrease (hα7, hα4β4 nACh receptors) to a marked increase (hα4β2 nACh receptors). Based on these findings, which differ from those showing that neither the affinity nor efficacy of nicotine, 3-(2-azetidinylmethoxy)-pyridine or epibatidine are greatly affected by halogenation, dehalogenation or halogen exchange at equivalent positions, we suggest that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobic agonist-binding pocket of the receptors.

U2 - 10.1016/S0028-3908(03)00025-X

DO - 10.1016/S0028-3908(03)00025-X

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