Fig. 3: Novel HCN inhibitors MS7710 and MS7712 exhibit improved BBB permeability compared to their parent compound Cilobradine. | Molecular Psychiatry

Fig. 3: Novel HCN inhibitors MS7710 and MS7712 exhibit improved BBB permeability compared to their parent compound Cilobradine.

From: Design and validation of novel brain-penetrant HCN channel inhibitors to ameliorate social stress-induced susceptible phenotype

Fig. 3: Novel HCN inhibitors MS7710 and MS7712 exhibit improved BBB permeability compared to their parent compound Cilobradine.

a Experimental timeline for BBB permeability testing in stress-naïve, male and female, C57BL/6 mice – brain and blood samples were taken at time points 15 min, 1 h, and 4 h post-IP injection of 20 mg/kg of each compound. b Schematic of sample collection. c Cilobradine brain and plasma concentrations for male mice (n = 3/timepoint/condition, ANOVA F(condition)1,12 = 148.6, *** p < 0.0001, F(time)2,12 = 15.73, *** p = 0.0004, F(time x condition)2,12 = 12.80, ** p = 0.0011) and ratio of 0.076. d MS7710 brain and plasma concentrations for male mice (n = 3/timepoint/condition, ANOVA F(condition)1,12 = 21.28, *** p = 0.0006, F(time)2,12 = 58.25, *** p < 0.0001, F(time x condition)2,12 = 5.663, * p = 0.0185) and ratio of 0.42. e MS7712 brain and plasma concentrations for male mice (n = 3/timepoint/condition, ANOVA F(condition)1,12 = 1.062, p ns, F(time)2,12 = 692.7, *** p < 0.0001, F(time x condition)2,12 = 12.97, ** p = 0.0010) and ratio of 0.86. f Cilobradine brain and plasma concentrations for female mice (n = 3/timepoint/condition, ANOVA F(condition)1,12 = 426.9, *** p < 0.0001, F(time)2,12 = 91.61, *** p < 0.0001, F(time x condition)2,12 = 85.77, *** p < 0.0001) and ratio of 0.029. g MS7710 brain and plasma concentrations and ratio of 0.21 for female mice (n = 3/timepoint/condition, ANOVA F(condition)1,12 = 783.1, *** p < 0.0001 F(time)2,12 = 1014, *** p < 0.0001, F(time x condition)2,12 = 377.8, *** p < 0.0001). h MS7712 brain and plasma concentrations and ratio of 0.34 for female mice (n = 3/timepoint/condition, ANOVA F(condition)1,12 = 195.6, *** p < 0.0001, F(time)2,12 = 469.3, *** p < 0.0001, F(time x condition)2,12 = 59.09, *** p < 0.0001). Data represented by mean ± SEM.

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