UNC9995 is a β-Arrestin2-biased Drd2 Agonist for Neurological Disease

Dopamine Receptors belong the family of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). There are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. The D1 and D5 receptors are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4receptors are members of the D2-like family. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors. Dopamine receptors play an important role in many neurological processes, including motivation, pleasure, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. Thus, dopamine receptors are common neurologic drug targets. The D2 dopamine receptor (DRD2) is a therapeutic target for Parkinson’s disease and antipsychotic agents.

The receptors D1 and D2 exhibiting the highest expression density of all dopamine receptors in the human central nervous system. Further, there are several isoforms of the individual receptor subtypes. Perhaps, the best-studied and most medically important dopamine receptor is D2 (DRD2), which is the focus of therapeutic intervention for diseases such as psychosis and Parkinson’s. DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine, leading to stimulation of Gi and inhibition of adenylyl cyclase.

UNC9995 is a β-arrestin2-biased agonist of dopamine receptor DRD2.

UNC9995 enhances interaction between β-arrestin2 and NLRP3 to suppress NLRP3 inflammasome activation and thus prevents neuronal degeneration. Furthermore, UNC9995 activates the DRD2/β-arrestin2 signaling to prevent inflammation-related genes transcription-induced by JAK/STAT3. Therefore, UNC9995 can improve depressive behavior in mouse model, and improve astrocytes dysfunctions. What’s more, UNC9995 exhibits anti-inflammatory effects in IL-6-stimulated primary astrocytes.Specifically, UNC9995 prevents astrocytic loss induced by high concentration of IL-6.

All in all, UNC9995 is a β-arrestin2-biased agonist of DRD2 that has the potential for the research of Parkinson’s disease.


[1] Martel JC, et, al. Front Pharmacol. 2020 Jul 14;11:1003.

[2] Liu Y, et, al. J Neuroinflammation. 2022 Oct 1;19(1):240.