Abstract
In drug discovery and development, central nervous system (CNS) drugs should be delivered into brain. Nonetheless, drug permeability into brain may be blocked by the blood-brain barrier (BBB) due to the imperviousness of the tight junction between endothelial cells in CNS and excretion by MDR1 (P-gp) expressing in the apical (luminal) membrane of endothelial cells. However, SLC transporter-mediated transport at the BBB can solve this permeable problem. It is well-known that compounds possessing N-containing groups are transported into brain across the BBB. This transportation was suggested to be associated with amine transporters. Thus, transporter-consciously designed drugs which possess N-containing groups as transporter recognition unit can be effectively delivered into brain across the BBB. In this paper, possibility of CNS drugs based on transporter-conscious drug design is described.
Highlights
In drug discovery and development, permeability of drugs across the cell membrane is generally a serious problem to overcome
The blood-brain barrier (BBB) is essentially attributed to the imperviousness of the tight junction between endothelial cells in central nervous system (CNS) and excretion by Multidrug Resistance 1 (MDR1) (P-gp) expressing in the apical membrane of endothelial cells
18F-THK-5105 (6), 18F-THK-5117 (7), and 18F-THK-523 (8) are tau positron emission tomography (PET) imaging agents for Alzheimer’s disease [15]. These brain-penetrant compounds share common structural features possessing N-containing groups. These results suggested that N-containing groups functioned as transporter recognition unit towards transporters expressing at the BBB
Summary
In drug discovery and development, permeability of drugs across the cell membrane is generally a serious problem to overcome. CNS drugs must penetrate the BBB into brain. Transporters [3] can solve these problems. The BBB is essentially attributed to the imperviousness of the tight junction between endothelial cells in CNS and excretion by MDR1 (P-gp) expressing in the apical (luminal) membrane of endothelial cells. The tactic utilizing co-expressed SLC transporters in the apical (luminal) membrane of endothelial cells is one of alternative methods to deliver compounds such as drugs and imaging agents into brain across the BBB (Figure 1). Transporter-conscious drug design is very important [5]. In this short review, I will introduce the effective method of brain-penetrant drug design based on transporterconscious drug design
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