The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs

Bioorg Med Chem. 2013 Dec 1;21(23):7309-29. doi: 10.1016/j.bmc.2013.09.060. Epub 2013 Oct 5.

Abstract

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2(∗) nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β2(∗) nAChR. All evaluated compounds are partial agonists or antagonists at α4β2(∗), with reduced or no effects on α3β4(∗) with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.

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; Cytisine; 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, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Mice
  • Nicotinic Agonists / chemistry*
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / chemistry*
  • Nicotinic Antagonists / pharmacology
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship

Substances

  • Alkanes
  • Bridged Bicyclo Compounds, Heterocyclic
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • bispidine
  • nonane