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. (22nd April 2020)

• Record Type: Journal Article
• Authors: Giri, Rajan; Alberts, Ian; Harding, Wayne W.
• Is Part Of: Chemical biology & drug design. Volume 96:Number 2(2020)
• Page Start: 825
• Page End: 835
• Publication Date: 2020-04-22
• Subjects: 5‐HT6 -- benzazepine -- D1 -- docking -- dopamine receptor -- serotonin receptor; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13691
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: The novel 1, 3, 4, 11b‐tetrahydro‐1 H ‐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 (Ki = 5 nM), selective 5‐HT6 receptor ligands. Abstract : Rigidification of the D1 receptor selective 1‐phenylbenzaazewpine scaffold diminishes affinity for D1 and other dopamine receptors and affords novel 1, 3, 4, 11b‐tetrahydro‐1 H ‐fluoreno[9, 1‐ cd ]azepines with high affinity and selectivity for the 5‐HT6 receptor. Docking studies reveal important H‐bonding, salt bridge, and π–π interactions that contribute to the 5‐HT6 receptor affinity of the rigidified compounds.