Halogenated Cytisine Derivatives As Agonists At Human Neuronal Nicotinic Acetylcholine Receptor Subtypes
Department
neurobiology
Document Type
Article
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. © 2003 Elsevier Science Ltd. All rights reserved.
Publication Date
1-1-2003
Publication Title
Neuropharmacology
ISSN
00283908
Volume
44
Issue
4
First Page
503
Last Page
515
Digital Object Identifier (DOI)
10.1016/S0028-3908(03)00025-X
Recommended Citation
Slater, Y. E.; Houlihan, L. M.; Maskell, P. D.; Exley, R.; Bermúdez, I.; Lukas, R. J.; Valdivia, A. C.; and Cassels, B. K., "Halogenated Cytisine Derivatives As Agonists At Human Neuronal Nicotinic Acetylcholine Receptor Subtypes" (2003). Translational Neuroscience. 225.
https://scholar.barrowneuro.org/neurobiology/225