title: A σ(1) receptor pharmacophore derived from a series of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols (AHDs).
abstract: A library of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols (AHDs) was synthesized and subjected to competition binding assays at σ(1) and σ(2) receptors, as well as off-target screening of representative members at 44 other common central nervous system (CNS) receptors, transporters, and ion channels. Excluding 3 low affinity analogs, 31 ligands demonstrated nanomolar K(i) values for either σ receptor subtype. Several selective σ(1) and σ(2) ligands were discovered, with selectivities of up to 29.6 times for σ(1) and 52.4 times for σ(2), as well as several high affinity, subtype non-selective ligands. The diversity of structures and σ(1) affinities of the ligands allowed the generation of a σ(1) receptor pharmacophore that will enable the rational design of increasingly selective and potent σ(1) ligands for probing σ(1) receptor function.
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.forename: Miral
authors.initials: M
authors.lastname: Manoli
authors.forename: Munikumar Reddy
authors.initials: MR
authors.lastname: Doddareddy
authors.forename: David E
authors.initials: DE
authors.lastname: Hibbs
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017480:Receptors, sigma / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D001952:Bridged-Ring Compounds; D008024:Ligands; D017480:Receptors, sigma; D054852:Small Molecule Libraries; D000097605:Sigma-1 Receptor; C577881:4-azahexacyclo(5.4.1.0(2,6).0(3,10).0(5,9).0(8,11))dodecan-3-ol