Aromatic linker variations in novel dopamine D₂ and D₃ receptor ligands

Area of Science:

• Medicinal Chemistry
• Neuropharmacology
• Drug Discovery

Background:

• Dopamine D2-like receptors (D2R and D3R) are key targets for antipsychotic medications.
• Existing antipsychotics often feature an aliphatic linker between an amine and an acyl-like group.

Purpose of the Study:

• To design and synthesize novel dopamine D2 and D3 receptor ligands.
• To explore the impact of modifying the linker structure on receptor affinity.
• To identify new lead compounds for antipsychotic drug development.

Main Methods:

• Synthesis of 18 novel phenylmethyl and phenylethyl linker-based ligands.
• In vitro evaluation using radioligand displacement assays.
• Determination of binding affinities (pK_i) for D2R and D3R.

Main Results:

• All synthesized ligands exhibited modest nanomolar affinity for D2R and D3R.
• Compound 6c, N-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}phenyl)acetamide, displayed the highest affinity.
• Compound 6c showed pK_i values of 7.83 for D2R and 8.04 for D3R, with a slight preference for D3R.

Conclusions:

• Modification of the aliphatic linker in antipsychotic scaffolds can yield potent D2/D3 receptor ligands.
• Compound 6c represents a valuable reference structure for developing new D2R and D3R-targeting agents.
• This study provides a foundation for a new class of antipsychotic drug candidates.