title: Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors.
abstract: A series of pyridone ring-modified derivatives of (7R,9S)-(-)-cytisine were evaluated for affinity and functional activity at neuromuscular alpha1beta1gammadelta, ganglionic alpha3beta4, and central neuronal alpha4beta2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the alpha4beta2 subtype.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Fitch
authors.forename: Yumika
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Paul
authors.initials: P
authors.lastname: Klaperski
authors.forename: John W
authors.initials: JW
authors.lastname: Daly
authors.forename: Gunther
authors.initials: G
authors.lastname: Seitz
authors.forename: Daniela
authors.initials: D
authors.lastname: Gündisch
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001392:Azocines / Q000138:chemical synthesis* / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006219:Halogens; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D018722:Nicotinic Agonists; D011485:Protein Binding; D011807:Quinolizines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D006219:Halogens; D018722:Nicotinic Agonists; D011807:Quinolizines; D011978:Receptors, Nicotinic; C004712:cytisine; D000093843:Quinolizidine Alkaloids