Diverse arrestin-recruiting and endocytic profiles of tricyclic antipsychotics acting as direct α 2A adrenergic receptor ligands

• Published in: Neuropharmacology 2017-04, Vol.116, p.38-49
• Main Authors: Cottingham, Christopher, Che, Pulin, Zhang, Wei, Wang, Hongxia, Wang, Raymond X, Percival, Stefanie, Birky, Tana, Zhou, Lufang, Jiao, Kai, Wang, Qin
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - pharmacology; beta-Arrestin 1 - genetics; beta-Arrestin 1 - metabolism; beta-Arrestin 2 - genetics; beta-Arrestin 2 - metabolism; Caveolin 1 - metabolism; Chlorpromazine - pharmacology; Clozapine - pharmacology; Cyclic AMP - metabolism; Endocytosis - drug effects; Endocytosis - physiology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fluphenazine - pharmacology; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; HEK293 Cells; Humans; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Mice, Knockout; Molecular Docking Simulation; Norepinephrine - pharmacology; Receptors, Adrenergic, alpha-2 - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.12.004

The therapeutic mechanism of action underlying many psychopharmacological agents remains poorly understood, due largely to the extreme molecular promiscuity exhibited by these agents with respect to potential central nervous system targets. Agents of the tricyclic chemical class, including both antidepressants and antipsychotics, exhibit a particularly high degree of molecular promiscuity; therefore, any clarification of how these agents interact with specific central nervous system targets is of great potential significance to the field. Here, we present evidence demonstrating that tricyclic antipsychotics appear to segregate into three distinct groups based upon their molecular interactions with the centrally-important α adrenergic receptor (AR). Specifically, while the α AR binds all antipsychotics tested with similar affinities, and none of the agents are able to induce classical heterotrimeric G protein-mediated α AR signaling, significant differences are observed with respect to arrestin3 recruitment and receptor endocytosis. All antipsychotics tested induce arrestin3 recruitment to the α AR, but with differing strengths. Both chlorpromazine and clozapine drive significant α AR endocytosis, but via differing clathrin-dependent and lipid raft-dependent pathways, while fluphenazine does not drive a robust response. Intriguingly, in silico molecular modeling suggests that each of the three exhibits unique characteristics in interacting with the α AR ligand-binding pocket. In addition to establishing these three antipsychotics as novel arrestin-biased ligands at the α AR, our findings provide key insights into the molecular actions of these clinically-important agents.