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

• Published in: Frontiers in pharmacology 2020-07, Vol.11, p.1005-1005
• Main Authors: Kozak, Rouba, Kiss, Tamás, Dlugolenski, Keith, Johnson, David E., Gorczyca, Roxanne R., Kuszpit, Kyle, Harvey, Brian D., Stolyar, Polina, Sukoff Rizzo, Stacey J., Hoffmann, William E., Volfson, Dmitri, Hajós, Mihaly, Davoren, Jennifer E., Abbott, Amanda L., Williams, Graham V., Castner, Stacy A., Gray, David L.
• Format: Article
• Language: English
• Subjects: Parkinson’s disease; Pharmacology; prefrontal cortex; pro-cognitive therapeutics; schizophrenia; working memory
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.01005

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.