Halogenated Cytisine Derivatives As Agonists At Human Neuronal Nicotinic Acetylcholine Receptor Subtypes
Cytisine (cy) is a potent and competitive partial agonist at Î±4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric Î±7-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) Î±7, hÎ±4Î²2 and hÎ±4Î²4 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 hÎ±7, hÎ±4Î²2 and hÎ±4Î²4 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 (hÎ±7, hÎ±4Î²4 nACh receptors) to a marked increase (hÎ±4Î²2 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. Â© 2003 Elsevier Science Ltd. All rights reserved.
Digital Object Identifier (DOI)
Slater, Y. E.; Houlihan, L. M.; Maskell, P. D.; Exley, R.; BermÃºdez, I.; Lukas, R. J.; Valdivia, A. C.; and Cassels, B. K., "Halogenated Cytisine Derivatives As Agonists At Human Neuronal Nicotinic Acetylcholine Receptor Subtypes" (2003). Neurobiology. 225.