PF-06256142 is a Selective and BBB Penetrated Orthosteric Agonist of the D1 Receptor

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the central nervous system (CNS) of vertebrates. Specifically, dopamine receptors not only activate different effectors through G-protein coupling but also activate signals through different protein interactions. Besides, the neurotransmitter dopamine is the main endogenous ligand of the dopamine receptor. Dopamine receptors are relevant to many nervous system processes. Moreover, Abnormal dopamine receptor signals and dopaminergic nerve functions are associated with a variety of neuropsychiatric diseases. Therefore, the dopamine receptor is a common target of neuro drugs.

There are at least five subtypes of dopamine receptors: D1, D2, D3, D4, and D5. Furthermore, Dopamine receptor D1 and dopamine receptor D5 are GS coupled receptors. D1 receptor activation and D2 receptor blockade also increase mRNA translation through phosphorylation of ribosomal protein S6, thus activating mTOR. Meanwhile, activated D1 receptors signal through GS subunits and increase intracellular cAMP. Nonetheless, D2 receptors signal through GI, which reduces cAMP level in cells. Importantly, D1 receptors play a central role in specific areas of synaptic plasticity, basal ganglia mediated motor function, and cognitive function. Here, we will introduce a potent and selective orthosteric agonist of the D1 receptor, PF-06256142.

PF-06256142 is a Selective and BBB Penetrated Orthosteric Agonist of the D1 Receptor.

First of all, PF-06256142 is a potent and selective orthosteric agonist of the D1 receptor, with an EC50 and Ki of 33 nM and 12 nM, respectively. Under the following four targets, the IC50 values of PF-06256142 as an antagonist were < 5 μM; M1, 4.9 μM; CB1, 2.1 μM; H1, 4.6 μM; Nav 1.5, 1.1μM. Particularly, PF-06256142 has an IC50 of 12 μM for HERG. Obviously, PF-06256142 has a D5 Ki of 4.8 nM. However, it has excellent selectivity (Ki>10 μM) relative to D2.

In the second place, PF-06256142 has good physical and chemical properties for CNS penetration. Interestingly, Low MDR and BCRP efflux ratio, high cell permeability and low turnover rate of human liver microsomes (HLM) contribute to its good characteristics. Interestingly, PF-06256142 has excellent brain utility, good venous clearance and half-life, and high oral bioavailability in rats.

All in all, PF-06256142 is a selective and BBB penetrated orthosteric agonist of the D1 receptor.


Davoren JE, et al. J Med Chem. 2018 Nov 15.