Characterization of PF-6142, a Novel, Non-Catecholamine Dopamine Receptor D1 Agonist, in Murine and Nonhuman Primate Models of Dopaminergic Activation

Abstract

Selective activation of dopamine D1 receptors remains a promising pro-cognitive therapeutic strategy awaiting robust clinical investigation. PF-6142 is a key example from a recently disclosed novel series of non-catechol agonists and partial agonists of the dopamine D1/5 receptors (D1R) that exhibit pharmacokinetic (PK) properties suitable for oral delivery. Given their reported potential for functionally biased signaling compared to known catechol-based selective agonists, and the promising rodent PK profile of PF-6142, we utilized relevant in vivo assays in male rodents and male and female non-human primates (NHP) to evaluate the pharmacology of this new series. Studies in rodents showed that PF-6142 increased locomotor activity and prefrontal cortex acetylcholine release, increased time spent in wakefulness, and desynchronized the EEG, like known D1R agonists. D1R selectivity of PF-6142 was supported by lack of effect in D1R knock-out mice and blocked response in the presence of the D1R antagonist SCH-23390. Further, PF-6142 improved performance in rodent models of NMDA receptor antagonist-induced cognitive dysfunction, such as MK-801-disrupted paired-pulse facilitation, and ketamine-disrupted working memory performance in the radial arm maze. Similarly, PF-6142 reversed ketamine-induced deficits in NHP performing the spatial delayed recognition task. Of importance, PF-6142 did not alter the efficacy of risperidone in assays predictive of antipsychotic-like effect in rodents including pre-pulse inhibition and conditioned avoidance responding. These data support the continued development of non-catechol based D1R agonists for the treatment of cognitive impairment associated with brain disorders including schizophrenia.

Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect

“…Over the past decade, much of the focus on D1Rs in schizophrenia has been on augmenting their signaling to promote cognition [56][57][58][59] . This idea is largely based on foundational work showing that, in schizophrenia, dopamine transmission is decreased within the prefrontal cortex, p. 16 where D1Rs are enriched and their signaling is crucial for cognitive function 60,61 .…”

Cognitive Deficit in Schizophrenia: From Etiology to Novel Treatments

“…Most dopamine receptors in DLPFC neurons are D 1 receptors, which co-localize in dendritic spines with hyperpolarization-activated cyclic nucleotide-gated potassium channels (KCNQ1), whose dysfunction seem to be related to schizophrenia [ 191 ]. Because the relationship between dopaminergic neurotransmission and cognition follows an inverted U-shaped curve, both D 1 agonists and antagonists have been assayed in animal models of schizophrenia as cognitive enhancers [ 192 , 193 ]. As dopaminergic neurotransmission refines the synaptic signals that reach the dendrites, the effect of dopaminergic drugs depends on the baseline levels of dopamine in the prefrontal cortex [ 194 ].…”

Functional Selectivity of Dopamine D1 Receptor Signaling: Retrospect and Prospect

“…Functional selectivity is currently a hot topic in the drug discovery field. Recently, several novel, functionally selective D 1 ligands were reported [ 92 , 93 ]. They all were biased toward cAMP compared to β-arrestin signaling.…”