D₂ Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine

Area of Science:

• Pharmacology
• Neuroscience
• Medicinal Chemistry

Background:

• Functionally selective G protein-coupled receptor (GPCR) ligands are crucial for dissecting signaling pathways linked to therapeutic effects and adverse drug reactions.
• Previous work identified G_i/o-biased and β-arrestin2-biased D₂ receptor (D2R) agonists derived from aripiprazole.
• Understanding structure-activity relationships is key to developing targeted GPCR modulators.

Purpose of the Study:

• To conduct a structure-functional selectivity relationship study based on the FDA-approved drug cariprazine.
• To discover novel D2R ligands with biased signaling profiles.
• To characterize the selectivity of novel compounds for specific D2R signaling pathways (G_i/o vs. β-arrestin2) and receptor subtypes (D2R vs. D3R).

Main Methods:

• Synthesis and pharmacological evaluation of novel compounds based on cariprazine.
• Assessment of G_i/o and β-arrestin2 signaling pathway activation at D2R.
• Determination of receptor subtype selectivity (D2R vs. D3R).
• Molecular docking studies to predict ligand-receptor interactions.
• In vivo studies in mice to assess D2R occupancy and behavioral effects.

Main Results:

• Compound 38 (MS1768) was identified as a potent D2R partial agonist with selectivity for the G_i/o pathway over β-arrestin2.
• Compound 38 demonstrated selective agonist activity for D2R over D3R, contrasting with the dual activity of cariprazine.
• Compound 38 potently antagonized dopamine-stimulated β-arrestin2 recruitment to D2R.
• Docking studies suggested unique binding interactions for compound 38, distinct from known β-arrestin2-biased ligands.
• In vivo studies confirmed high D2R occupancy and effective inhibition of hyperlocomotion in mice.

Conclusions:

• Compound 38 represents a novel D2R ligand with functional selectivity for G_i/o signaling and D2R over D3R.
• The distinct binding mode of compound 38 may explain its biased signaling profile.
• This selective ligand serves as a valuable tool for investigating D2R signaling in physiological and pathological contexts.
• Compound 38's profile suggests potential therapeutic applications with a reduced side effect burden related to β-arrestin2 pathways.