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

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 (M6B, M5B and M4B) 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 simulations (MDS) provided further mechanistic insights into their interactions with D2-like receptors. AM-G exhibited potential as a strong D3R/D4R antagonist, whereas M6B and M5B showed higher affinity 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.