Insights into the structural determinants required for high-affinity binding of chiral cyclopropane-containing ligands to α4β2-nicotinic acetylcholine receptors: An integrated approach to behaviorally active nicotinic ligands

Han Kun Zhang, J. Brek Eaton, Li Fang Yu, Mieke Nys, Angelica Mazzolari, René Van Elk, August B. Smit, Vadim Alexandrov, Taleen Hanania, Emily Sabath, Allison Fedolak, Daniela Brunner, Ronald J. Lukas, Giulio Vistoli, Chris Ulens, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a cocrystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine a previous model of the human α4β2- nAChR, thus possibly providing a better understanding of the structure of the human receptor. To validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogues of compound 5. The most promising compound, 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral end points in the rodent studies.

Original languageEnglish (US)
Pages (from-to)8028-8037
Number of pages10
JournalJournal of medicinal chemistry
Volume55
Issue number18
DOIs
StatePublished - Sep 27 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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