High-potency Fluorenol analogs: Achieving Binding Energies Exceeding –10.7 kcal/mol. Molecular Docking of Selective analogs Dopamine D1A Receptor.

Fluorenol is a specific nootropic with a mild dopaminergic effect. It binds gently to the dopamine receptor D1A as an agonist at D-103, using the hydroxyl group for hydrogen bonding without an ionic component (Figure 1) with a low affinity of –8.1 kcal/mol. This, combined with the mild hydrogen bonding of the alcohol, results in a mild effect characteristic of the alcohol group. Fluorenol is ineffective in docking the D2A receptor, which is also a positive characteristic of the fluorene core. However, this agonism, coupled with its low affinity, requires significant dosages, which are close to the safe dosage threshold for fused lipophilic aromatic derivatives. Therefore, the search for tautomers, derivatives, and new cores with similar characteristics is a standard tactic, which was used for docking the analogs. In addition, increasing nuclear affinity promotes more complete direct agonism while minimizing the contribution of reuptake blockade, thus reducing the amount of non-selective dopamine released. We designed structures with affinities greater than -9 kcal/mol and -10.7 kcal/mol, efficiently binding D103 to the hydroxyl group, the weak 1,2,4-triazoles(IIb) nitrogen, the weak 1,2,4-oxadiazoles nitrogen, and the moderately strong imidazoles nitrogen for binding to carboxylic acid residues. We thus obtained a gradient of derivatives and analogs, from the most active to the most potent in all respects. We also obtained new selectivity data, since some of the most spatially specific structures for the D1A receptor are inactive on the D2A receptor or are unable to penetrate the D2A receptor. Some highly active derivatives and analogs are somewhat less accessible for organic synthesis than fluorenol, while others are equally accessible and even more accessible, with high affinity values and full compliance with the pharmacological profile of fluorenol. The calculated doses of fluorenol derivatives and analogues with an affinity of -9-10.7 kcal/mol presented in the work can vary from tens to several milligrams, which eliminates issues with accumulation and acute and subacute toxicity.