title: Bioisosteric replacement leading to biologically active [2.2]paracyclophanes with altered binding profiles for aminergic G-protein-coupled receptors.
abstract: Exploring the chemical diversity space of GPCR ligands, we recently discovered [2.2]paracyclophanes as valuable atypical bioisosteres for secondary affinity and selectivity generating moieties. To find out if such an exchange also works for structural moieties that simulate the endogenous neurotransmitter, π1 or π2 or both systems π1 and π2 of three representative privileged structures of types 1, 2, and 3 were replaced by a [2.2]paracyclophane unit. Contributions of the respective functionalities to the binding affinities of a panel of relevant monoaminergic GPCRs were systematically examined. The study led to the paracyclophanylpiperazine 3a displaying excellent D(3) affinity (K(i) = 1.6 nM) and a strongly attenuated binding to D(4), 5-HT(1) and α(1). Whereas functional experiments showed neutral D(3) antagonist properties, mutagenesis studies indicated a binding mode that is similar to its lead compounds of type 3.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
authors.forename: Marika
authors.initials: M
authors.lastname: Skultety
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008024:Ligands; C553298:N-(4-(4-((2.2)paracyclophan-4-yl)piperazin-1-yl)butyl)benzo(b)thiophenyl-2-carboxamide; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D013876:Thiophenes