The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor (nAChR) ligands. Part 1: the influence of different hydrogen bond acceptor systems on alkyl and (hetero)aryl substituents

Bioorg Med Chem. 2013 Dec 1;21(23):7283-308. doi: 10.1016/j.bmc.2013.09.059. Epub 2013 Oct 5.

Abstract

3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2(∗) were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2(∗) possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents.

Keywords: 1,2-dimethoxyethane; 3,7-Diazabicyclo[3.3.1]nonane; 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; 4-(dimethylamino)pyridine; BBB; Bispidine; CD(3)OD; CDCl(3); CH(2)Cl(2); CNS; D(2)O; DCC; DMAP; DME; DMF; Et(2)O; Et(3)N; EtOAc; HBA; HCl; HEPES; HEPES-buffered salt solution; HSS; K(2)CO(3); KBr; KMnO(4); KOH; MeCN; MeI; MeOH; MgSO(4); N,N-dimethylformamide; N,N′-dicyclohexylcarbodiimide; NaHCO(3); NaOH; Nicotinic acetylcholine receptor; PE; PEI; Pd/C; Ro5; Structure–activity relationship; THF; TPSA; TRIS; ZnBr(2); acetonitrile; blood–brain barrier; central nervous system; deuterium oxide; deuterochloroform; dichloromethane; diethyl ether; ethyl acetate; hydrogen bond acceptor; hydrogen chloride; iodomethane; magnesium sulfate; methanol; nAChR; nicotinic acetylcholine receptor; palladium on activated charcoal; petroleum ether; poly(ethyleneimine); potassium bromide; potassium carbonate; potassium hydroxide; potassium permanganate; rule of five; sodium hydrogen carbonate; sodium hydroxide; tetradeuteromethanol; tetrahydrofuran; topological polar surface area; tri(hydroxymethyl)aminomethane; triethylamine; zinc bromide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkanes / chemistry*
  • Alkanes / pharmacology
  • Animals
  • Bridged Bicyclo Compounds / chemistry*
  • Bridged Bicyclo Compounds / pharmacology
  • Cattle
  • Cell Line
  • Hydrogen Bonding
  • Ligands
  • Mice
  • Nicotinic Agonists / chemistry*
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / chemistry*
  • Nicotinic Antagonists / pharmacology
  • Rats
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship
  • Torpedo
  • Xenopus

Substances

  • Alkanes
  • Bridged Bicyclo Compounds
  • Ligands
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • nonane