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.
Highlights
D1 receptors (D1Rs) play a central role in important domains of cognitive function including spatial learning and memory, reversal, extinction, and incentive learning (Huang and Kandel, 1995; Rascol et al, 1999; Goldman-Rakic et al, 2000; Seamans et al, 2001; Williams and Castner, 2006; Takahashi et al, 2012; Wass et al, 2013) and D1/5 receptors (D1R) expression or signaling are compromised in a variety of psychiatric, neurological, and endocrine disorders including schizophrenia, drug addiction, and Parkinson’s disease (Haney et al, 1998; Wang et al, 1998; Mailman et al, 2001; Rosell et al, 2015; Papapetropoulos et al, 2018)
An analysis of the time course data indicates that treatment with vehicle followed by PF6142 on day 5 [vehicle + PF-6142 group on Figure 1A] increased cortical ACh levels in dose dependent manner post-dose as compared to 5 d of vehicle treatment [vehicle + vehicle group seen in Figure 1A, F(treatment)2, 19 = 24.74, p = 0.0101, F(time)17, 323 = 17.76, p < 0.0001, F(interaction)3, 42 = 6.224, p = 0.023]
Prefrontal cortical (PFC) functional alterations have been associated with the symptoms of multiple neuropsychiatric and neurodegenerative diseases, such as schizophrenia and Parkinson’s disease (Howes and Kapur, 2009)
Summary
D1 receptors (D1Rs) play a central role in important domains of cognitive function including spatial learning and memory, reversal, extinction, and incentive learning (Huang and Kandel, 1995; Rascol et al, 1999; Goldman-Rakic et al, 2000; Seamans et al, 2001; Williams and Castner, 2006; Takahashi et al, 2012; Wass et al, 2013) and D1R expression or signaling are compromised in a variety of psychiatric, neurological, and endocrine disorders including schizophrenia, drug addiction, and Parkinson’s disease (Haney et al, 1998; Wang et al, 1998; Mailman et al, 2001; Rosell et al, 2015; Papapetropoulos et al, 2018). Studies conducted by Sawaguchi and Goldman-Rakic using both agonists and antagonists (Sawaguchi et al, 1990; Sawaguchi and Goldman-Rakic, 1994) indicated that the modulation of working memory processes by mesocortical DA in primates is primarily mediated by D1Rs. Local administration of D1R antagonists into the dorsolateral prefrontal cortex (PFC) induced deficits in a working memory task whereas blockade of D2-like receptors gave no impairment. Subsequent studies revealed that a primary function of D1R activation is to enhance and stabilize task-related activity of PFC neurons (Williams and Goldman-Rakic, 1995). D1R agonist therapy may ameliorate cognitive impairment by enhancing insufficient DA tone in the PFC of patients with schizophrenia (Abi-Dargham and Moore, 2003; Goldman-Rakic et al, 2004; Williams and Castner, 2006; Granado et al, 2008)
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