1181802-58-3Relevant articles and documents
Bioisosteric replacement leading to biologically active [2.2]Paracyclophanes with altered binding profiles for aminergic g-protein-coupled receptors
Skultety, Marika,Hübner, Harald,L?ber, Stefan,Gmeiner, Peter
experimental part, p. 7219 - 7228 (2010/12/25)
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 D3 affinity (Ki = 1.6 nM) and a strongly attenuated binding to D4, 5-HT1 and α1. Whereas functional experiments showed neutral D3 antagonist properties, mutagenesis studies indicated a binding mode that is similar to its lead compounds of type 3.
