Evaluation of blood-brain barrier and blood-cerebrospinal fluid barrier permeability of 2-phenoxy-indan-1-one derivatives using in vitro cell models

Abstract

2-Phenoxy-indan-1-one derivatives (PIOs) are a series of novel central-acting cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The adequate distribution of PIOs to the central nervous system (CNS) is essential for its effectiveness. However, articles related with their permeability in terms of CNS penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) have not been found. This study was undertaken to evaluate the in vitro BBB and BCSFB transport of PIOs using Madin-Darby canine kidney (MDCK), MDCK-MDR1 and Z310 cell line models. As a result, the transepithelial transport of PIOs did not differ between MDCK and MDCK-MDR1, and the result suggested that PIOs were not substrates for P-gp, which means that multidrug resistance (MDR) function would not affect PIOs absorption and brain distribution. High permeability of PIOs in Z310 was found and it suggested that PIOs had high brain uptake potential. The experiment also showed that PIOs had inhibitory effects on the MDR1-mediated transport of Rhodamine123 with an IC50 value of 40-54 μM. And we suggested that 5,6-dimethoxy-1-indanone might be the pharmacophoric moiety of PIOs that interacts with the binding site of P-gp.

Keywords: 2-Phenoxy-indan-1-one derivatives; 2-phenoxy-indan-1-one derivatives; AChE; AD; ADME; AIC(c); AP; Akaike's Information Criterion; Alzheimer's disease; BBB; BCSFB; BL; Bi-directional transport; Blood–brain barrier; Blood–cerebrospinal fluid barrier; CNS; CP; CSF; DMEM; DMSO; Dulbecco's modified Eagle's medium; FBS; HBSS; Hank's balanced salt solution; MDCK; MDR; Madin–Darby canine kidney; NCEs; P(app); P-glycoprotein; P-gp; PIOs; TEA; TEER; absorption, distribution, metabolism, and excretion; acetylcholinesterase; apical; apparent permeability coefficients; basolateral; blood–brain barrier; blood–cerebrospinal fluid barrier; central nervous system; cerebrospinal fluid; choroid plexus; dimethylsulfoxide; fetal bovine serum; multidrug resistance; new chemical entities; transepithelial electrical resistance; triethylamine.