title: 7-Azabicyclo[2.2.1]heptane as a scaffold for the development of selective sigma-2 (σ2) receptor ligands.
abstract: A series of N-substituted 7-azabicyclo[2.2.1]heptanes (12-17 and 22-25) and similarly substituted pyrrolidines (32-36 and 41-44) were synthesized as sterically-reduced, achiral analogs of adamantane- and trishomocubane-derived σ ligands. In vitro competition binding assays against σ receptors revealed that arylalkyl N-substituents conferred selectivity for the σ(2) subtype, while alicyclic or polycarbocyclic substituents imparted high affinity for both subtypes. The σ(2) binding and subtype selectivities of N-arylalkyl-7-azanorbornanes was generally greater than the analogously-substituted pyrrolidines, indicating that steric bulk and conformational restriction around the nitrogen atom are likely important for subtype discrimination.
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.forename: Louis M
authors.initials: LM
authors.lastname: Rendina
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000218:Adamantane / Q000737:chemistry; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D001923:Brain Chemistry; D006536:Heptanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014020:Tissue Extracts / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D053961:Azabicyclo Compounds; D006536:Heptanes; D008024:Ligands; D011759:Pyrrolidines; D017480:Receptors, sigma; D014020:Tissue Extracts; C106107:sigma-2 receptor; D009584:Nitrogen; D000218:Adamantane