Bioisosteric Replacement Leading to Biologically Active [2.2]Paracyclophanes with Altered Binding Profiles for Aminergic G-Protein-Coupled Receptors

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. In find out if such an exchange also works for structural moieties that simulate the endogenous neurotransmitter, pi 1 or pi 2 or both systems pi 1 and pi 2 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 at 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-HT1 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.