2. Academic Validation
  3. Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors

Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors

  • Bioorg Med Chem Lett. 2005 Feb 15;15(4):1221-4. doi: 10.1016/j.bmcl.2004.11.073.
Richard W Fitch 1,  Yumika Kaneko,  Paul Klaperski,  John W Daly,  Gunther Seitz,  Daniela Gündisch
Affiliations

Affiliation

  • 1 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.
PMID: 15686946 DOI: 10.1016/j.bmcl.2004.11.073
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.

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