Diazaspirocyclic compounds as selective ligands for the α4β2 nicotinic acetylcholine receptor

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 15; pp. 5089 - 5092
• Main Authors: Strachan, Jon-Paul, Farias, Jarrett J., Zhang, Jenny, Caldwell, William S., Bhatti, Balwinder S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.08.2012; Elsevier
• Subjects: acetylcholine; antagonists; Aza Compounds - chemistry; Biological and medical sciences; chemistry; Diazaspirocyclic; ganglia; heptane; Heptanes - chemistry; Humans; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; muscles; Nicotinic; Nicotinic Antagonists - chemical synthesis; Nicotinic Antagonists - chemistry; Nicotinic Antagonists - metabolism; nuclear magnetic resonance spectroscopy; Pharmacology. Drug treatments; Protein Binding; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - metabolism; α4β2; Nicotinic; α4β2; Diazaspirocyclic; Cholinergic receptor; Ligand; α4 nicotinic receptor; Selectivity; Nicotinic receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.108

Diazaspirocyclic ligands have been synthesized in four steps as selective α4β2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2′-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (Ki<35nM) at the human α4β2 nAChR subtype, and very low affinity for the human α7, α3β4 (ganglion) and α1β1γδ (muscle) subtypes (Ki>500nM).