Structural Requirements for Uptake of Diphenhydramine Analogs into hCMEC/D3 Cells Via the Proton-Coupled Organic Cation Antiporter

There is increasing evidence that a proton-coupled organic cation (H+/OC) antiporter facilitates uptake of various central nervous system-active drugs, such as the histamine H1 receptor antagonist diphenhydramine, into brain. The purpose this study was to clarify structural requirements for H+/OC antiporter-mediated hCMEC/D3 cells, an established in vitro model human blood-brain barrier, by using series diphenhydramine analogs. For purpose, we synthesized seven tertiary amine analogs and three amide Uptake all amines facilitated outwardly directed H+ gradient inhibited pyrilamine, typical substrate strong inhibitor antiporter. Further, most trans-stimulated pyrilamine. 21 times faster than amides on average, even though lipophilicity (log D7.4) lower amides. Amines containing pyrrolidine or piperidine ring showed highest rates. Our results suggest moiety, especially heterocyclic important recognition transport