Design, synthesis, drug-likeness, and molecular dynamics evaluations of monobrominated amathamide G analogs as potential ligands for D2-like dopamine receptors

Abstract Dopamine receptors (DRs) are key modulators of physiological and behavioral responses in the central nervous system (CNS), playing a major role in psychotic disorders. Among these, the D2-like members D2R, D3R and D4R are particularly attractive therapeutic targets for the development of novel compounds derived from both synthetic and natural sources. The marine bryozoan Amathia produces alkaloids known as amathamides (A-H), among which the tribrominated amathamide G (AM-G) stands out as a promising scaffold. Its benzene–aliphatic linker–pentacyclic structure is reminiscent of standard dopamine antagonists such as eticlopride (ETI). In this study, a debrominated (AM-0) and monobrominated derivatives (M4B, M5B and M6B) were successfully synthesized and purified. As an initial preclinical assessment, the drug likeness profiles of these compounds were predicted and analyzed based on physicochemical properties, medicinal chemistry, and pharmacokinetic parameters. The analysis revealed that debromination of AM-G improves both lipid and aqueous solubility, enhances overall drug desirability across four major medicinal chemistry rule sets, and predicts better CNS penetration, bioavailability, half-life, and clearance, while maintaining a relatively low risk of carcinogenicity. Molecular docking and molecular dynamics (MD) simulations suggested a differential affinity amongst amathamide G derivatives towards D2-like receptors. Specifically, AM-G behaved as a high-affinity putative ligand for D3R/D4R, whereas M5B and M6B showed selectivity for D2R. These findings support continued in vitro and in vivo evaluation of these compounds, particularly in models involving expression, structure-based variations, and pathologies associated with D2R-like receptors.