title: The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: carboxamide derivatives with different spacer motifs.
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.
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Eibl
authors.forename: Lenka
authors.initials: L
authors.lastname: Munoz
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tomassoli
authors.forename: Clare
authors.initials: C
authors.lastname: Stokes
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: Daniela
authors.initials: D
authors.lastname: Gündisch
mesh_terms: D000473:Alkanes / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000473:Alkanes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C495809:bispidine; C017573:nonane
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