High affinity rigidified AT₂ receptor ligands with indane scaffolds

Figures

• 

  Fig. 1. Structures of compounds 1–6.

• 

  Fig. 2. Structures of compounds 7a/b, 8a/b, 9a/b, 10a/b.

• 

  Scheme 1. Reagents: (a) 2-propylmagnesium bromide, diethyl ether, toluene, HCl (aq); (b) H2 (40 psi), PtO2, ethanol; (c) chlorosulfonic acid, DCM; (d) tert-butylamine, DCM.

• 

  Scheme 2. Reagents: (a) n-BuLi, THF, triisopropyl borate, HCl (aq); (b) Pd(PPh3)4, Na2CO3, toluene, ethanol, H2O; (c) BCl3, DCM; (d) n-butyl chloroformate, Na2CO3, DCM, H2O.

• 

  Scheme 3. Reagents: (a) n-BuLi, THF, triisopropyl borate, HCl (aq); (b) Pd(PPh3)4, Na2CO3, toluene, ethanol, H2O; (c) BCl3, DCM; (d) n-butyl chloroformate, Na2CO3, DCM, H2O.

• 

  Fig. 3. Effect of compounds 7a/b and 8a/b on neurite outgrowth in NG108-15 cells. The cells were plated at a cell density of 3.6 × 104 cells/Petri dishes (35 mm) and were cultured for three days in the absence or presence of 100 nM Ang II, 10 nM 7a, 10 nM 7b, 10 nM 8a or 10 nM 8b alone or in combination with 10 μM PD 123319 or 100 nM Ang II. Cells with at least one neurite longer than a cell body were counted as positive for neurite outgrowth. The number of cells with neurites was expressed as the percentage of the total number in the micrographs (at least 400 cells according to the experiment). The results are significant according to two-way ANOVA: ****, p < 0.0001; ***, p < 0.001; **, p < 0.01; ns = not significant.

• 

  Fig. 4. Effect of compounds 9a/b and 10a/b on neurite outgrowth in NG108-15 cells. The cells were plated at a cell density of 3.6 × 104 cells/Petri dishes (35 mm) and were cultured for three days in the absence or presence of 100 nM Ang II, 10 nM 9a, 10 nM 9b, 10 nM 10a or 10 nM 10b alone or in combination with 10 μM PD 123319 or 100 nM Ang II. Cells with at least one neurite longer than a cell body were counted as positive for neurite outgrowth. The number of cells with neurites was expressed as the percentage of the total number in the micrographs (at least 400 cells according to the experiment). The results are significant according to two-way ANOVA: ****, p < 0.0001; ***, p < 0.001; **, p < 0.01; ns = not significant.

• 

  Fig. 5. Overview over the investigated structures and their biological activities at the AT2 receptor.

• 

  Fig. 6. Low energy conformations of enantiomer pairs superimposed visualizing the small structural difference between an agonist and an antagonist. Left: Model compounds of 7a (–) (agonist) and 7b (+) (antagonist) superimposed. Right: Model compounds of 10a (+) (antagonist) and 10b (–) (agonist) superimposed.