Synthesis, biological evaluation, and molecular modeling of ORM-10921 and its analogs as alpha(2C)-adrenoceptor antagonists

The a(2C)-adrenoceptor (a(2C)-AR) is regarded as one of the potential targets for antipsychotics. A few of structurally diverse a(2C)-AR antagonists have been reported, among which ORM-10921, containing one rigid tetracyclic framework with two neighboring chiral centers, has exhibited remarkable antipsychotic-like effects and pro-cognitive properties in different animal models. Yet the binding mode of ORM-10921 remains elusive. In this study, all of its four stereoisomers and a set of its analogs were synthesized and in vitro evaluated for their a(2C)-AR antagonist activities. The molecular docking study and hydration site analysis gave a rational explanation for the biological results, which might provide helpful insights into the binding mode and future optimization.