High affinity rigidified AT₂ receptor ligands with indane scaffolds

Rigidification of the isobutyl side chain of drug-like AT₂ receptor agonists and antagonists that are structurally related to the first reported selective AT₂ receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers <b>7a</b>, <b>7b</b>, <b>8a</b>, <b>8b</b>, <b>9a</b>, <b>9b</b>, <b>10a</b> and <b>10b</b> bind to the AT₂ receptor with moderate (<i>K</i> _i = 54-223 nM) to high affinity (<i>K</i> _i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives <b>7b</b> and <b>10a</b> are among the most potent AT₂ receptor antagonists reported so far. As illustrated by the enantiomer pairs <b>7a</b>/<b>b</b> and <b>10a</b>/<b>b</b>, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT₂ receptor, and can convert agonists to antagonists and <i>vice versa</i>.