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D1/D5 receptor agonists in ADHD

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D1/D5 receptor agonists in ADHD

Numerous studies showed that D1/D5 receptor agonists improve cognitive performance.1234

Problems that need to be resolved before D1/D5 agonists can be used as medications are oral absorption and duration of action

1. 2-Methyldihydrexidine

2-Methyldihydrexidine (SCH39266, 2MDHX) is a selective D1 and D5 receptor agonist.

In a study of SHR (spontaneouls(ly) hypertensive rat), an animal model of ADHD-HI, 2-methyldihydrexidine was compared with methylphenidate.5
SHR exhibit deficits in spatial working memory.
Methylphenidate (1.5 mg/kg) improved spatial working memory in half of the rats tested but impaired it in the other half.
The improvement and impairment mediated by MPH were reversed by direct administration of 2-methyldihydrexidine to the PFC

2-Methyldihydrexidine improved spatial working memory more than MPH, without the impairment observed with MPH in some of the animals
SHRs with lower output power (power before drug administration) improved more than SHRs with higher output power

2-Methyldihydrexidine altered the firing rate of single neurons, resulting in a change in neuronal preference for correct or incorrect behavioral responses. 2-Methyldihydrexidine decreased neuronal preference in animals whose behavior improved. In contrast, MPH decreased neuronal preference in animals whose performance was impaired.

2-Methyldihydrexidine is a complete agonist of adenylate cyclase and a super-agonist in β-arrestin recruitment. 2-Methyldihydrexidine therefore tends to target D1-mediated β-arrestin-related signaling.6
2-Methyldihydrexidine shows an inverted U dose dependence in modulating the neuronal activities of the PFC.
2-Methyldihydrexidine reduced neuron-to-neuron variation better than CY208,243 and appears to act more efficiently and potently overall than CY208,243

2. PF-3628

PF-3628 is a low-affinity D1 agonist.2
The low D1 affinity of PF-3628 is thought to make it more similar to natural dopamine action. PF-3628 only slightly affects β-arrestin signaling
Aged monkeys have a natural loss of dopamine and a natural reduction in neuronal excitation in the dlPFC and working memory performance. Direct administration of PF-3628 to dlPFC neurons from aged rhesus monkeys improved their performance in a delay-dependent working memory task.

3. CY208,243

CY208,243 shows relatively high intrinsic activity of adenylate cyclase and is a partial agonist of β-arrestin recruitment. CY208,243 thus tends to target D1-mediated cAMP signaling.6
CY208,243 shows an inverted U dose dependence in modulating the neuronal activities of the PFC
CY208,243 improved the strength of neuronal outcome sensitivity for working memory-related choice behavior in the T-maze, but reduced neuron-to-neuron variation worse than 2-methyldihydrexidine .
Overall, CY208,243 appears to be less efficient and less potent than 2-methyldihydrexidine.


  1. Kozak, Kiss, Dlugolenski, Johnson, Gorczyca, Kuszpit, Harvey, Stolyar, Sukoff Rizzo, Hoffmann, Volfson, Hajós, Davoren, Abbott, Williams, Castner, Gray (2020): Characterization of PF-6142, a Novel, Non-Catecholamine Dopamine Receptor D1 Agonist, in Murine and Nonhuman Primate Models of Dopaminergic Activation. Front Pharmacol. 2020 Jul 7;11:1005. doi: 10.3389/fphar.2020.01005. PMID: 32733245; PMCID: PMC7358525.

  2. Wang, Datta, Enwright, Galvin, Yang, Paspalas, Kozak, Gray, Lewis, Arnsten (2019): A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex. Neuropharmacology. 2019 May 15;150:46-58. doi: 10.1016/j.neuropharm.2019.03.001. PMID: 30858103; PMCID: PMC6475613.

  3. Yang Y, Lee SM, Imamura F, Gowda K, Amin S, Mailman RB (2021): D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex. Mol Psychiatry. 2021 Feb;26(2):645-655. doi: 10.1038/s41380-018-0312-1. PMID: 30532019.

  4. Arnsten, Girgis, Gray, Mailman (2017): Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry. 2017 Jan 1;81(1):67-77. doi: 10.1016/j.biopsych.2015.12.028. PMID: 26946382; PMCID: PMC4949134. REVIEW

  5. Yang Y, Lewis, Kong, Mailman (2022): A dopamine D1 agonist vs. methylphenidate in modulating prefrontal cortical working memory. J Pharmacol Exp Ther. 2022 Jun 5:JPET-AR-2022-001215. doi: 10.1124/jpet.122.001215. PMID: 35661631.

  6. Yang Y, Kocher, Lewis, Mailman (2022): Dose-Dependent Regulation on Prefrontal Neuronal Working Memory by Dopamine D1 Agonists: Evidence of Receptor Functional Selectivity-Related Mechanisms. Front Neurosci. 2022 Jun 16;16:898051. doi: 10.3389/fnins.2022.898051. PMID: 35784852; PMCID: PMC9244699.