Fancy bioisosteres: Novel paracyclophane derivatives as super-affinity dopamine D3 receptor antagonists

摘要

The exploration of the chemical diversity space depends on the discovery of novel bioisosteric elements. As a continuation of our project on bilayered arene surrogates, we herein report on [2.2]paracyclophanederived dopamine D3 receptor antagonists of type 4 and 6. For the most promising test compound 6a, bearing a 2-methoxyphenyl substituent, a stereocontrolled preparation was performed when the planar chirality of enantiomers (R)-6a (FAUC 418) and (S)-6a caused a considerable differentiation of D3 binding, which is indicated by K-i values of 0.19 and 3.0 nM, respectively. Functional experiments showed D3 antagonist properties for the paracyclophane derivatives of type 6. To elucidate putative bioactive low-energy conformations, DFT-based studies including the calculation of diagnostic magnetic shielding properties were performed. An 89% increase in volume for the [2.2] paracyclophane moiety compared to that of the monolayered benzofurane of lead compound 3b indicates higher plasticity of GPCR binding regions than usually expected.