Synthesis,pharmacological evaluations,and molecular docking studies on a new 1,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine framework: Rigidification of D1 receptor selective 1‐phenylbenzazepines and discovery of a new 5‐HT6 receptor scaffold

The novel 1,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine framework, a structurally rigidified variant of the 1‐phenylbenzazepine template, was synthesized via direct arylation as a key reaction. Evaluation of the binding affinities of the rigidified compounds across a battery of serotonin, dopamine, and adrenergic receptors indicates that this scaffold unexpectedly has minimal affinity for D₁ and other dopamine receptors and is selective for the 5‐HT₆ receptor. The affinity of these systems at the 5‐HT₆ receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D₁ receptor affinity of the rigidified compounds may be due in part to weaker H‐bonding interactions between the oxygenated moieties on the compounds and specific receptor residues. Key receptor–ligand H‐bonding interactions, salt bridges, and π–π interactions appear to be responsible for the 5‐HT₆ receptor affinity of the compounds. Compounds 10 (6,7‐dimethoxy‐2,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine) and 12 (6,7‐dimethoxy‐2‐methyl‐2,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine) have been identified as structurally novel, high affinity (K_i = 5 nM), selective 5‐HT₆ receptor ligands.