Bioisosteric replacement leading to biologically active [2.2]paracyclophanes with altered binding profiles for aminergic G-protein-coupled receptors.

Article Details

Citation

Skultety M, Hubner H, Lober S, Gmeiner P

Bioisosteric replacement leading to biologically active [2.2]paracyclophanes with altered binding profiles for aminergic G-protein-coupled receptors.

J Med Chem. 2010 Oct 14;53(19):7219-28. doi: 10.1021/jm100899z.

PubMed ID
20839776 [ View in PubMed
]
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, pi1 or pi2 or both systems pi1 and pi2 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 alpha(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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
HaloperidolDopamine D2 receptorKi (nM)1.1N/AN/ADetails
HaloperidolDopamine D2 receptorKi (nM)0.87N/AN/ADetails
HaloperidolDopamine D3 receptorKi (nM)7.5N/AN/ADetails