Dear reader of, please excuse the disruption. needs about $63500 in 2024. In 2023 we received donations of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 23,000 times a week, but only 75 people donate. If you find useful, please take a minute and support with your donation. Thank you!

Since 01.06.2021 is supported by the non-profit ADxS e.V..

$26199 of $63500 - as of 2024-06-30
Header Image
D1/D5 receptor agonists for ADHD


D1/D5 receptor agonists for ADHD

Numerous studies have shown that D1/D5 receptor agonists improve cognitive performance.12345
However, this is not the case for all D1/D5 agonists6

Problems that need to be solved before D1/D5 agonists can be used medicinally 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 on SHR (spontaneouls(ly) hypertensive rat), an animal model for ADHD-C, 2-methyldihydrexidine was compared with methylphenidate.7
SHR have 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 into the PFC.

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

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

2-Methyldihydrexidine is a full agonist of adenylate cyclase and a super-agonist in β-arrestin recruitment. 2-Methyldihydrexidine therefore tends to target D1-mediated β-arrestin-related signaling.8
2-Methyldihydrexidine shows an inverse 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 be more efficient and potent overall than CY208,243

2. PF-3628

PF-3628 is a low-affinity D1 agonist.2
The low D1 affinity of PF-3628 should make it more similar to the natural dopamine effect. PF-3628 has little effect on β-arrestin signaling.
Aged monkeys have a natural loss of dopamine and a natural decrease in neuronal excitation in the dlPFC and working memory performance. Direct administration of PF-3628 to dlPFC neurons of aged rhesus monkeys improved their performance in a delay-dependent working memory task.

3. CY208,243

CY208,243 shows a relatively high intrinsic activity of adenylate cyclase and is a partial agonist of β-arrestin recruitment. CY208,243 thus tends to be directed towards D1-mediated cAMP signaling8
CY208,243 shows an inverse 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.

4. Tavapadon (PF-06649751)

A Phase II study launched by patent holder Pfizer reports that tavapadone is superior to placebo in the treatment of Parkinson’s disease.9

  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. Balice-Gordon, Honey, Chatham, Arce, Duvvuri, Naylor, Liu W, Xie Z, DeMartinis, Harel, Braley, Kozak, Park L, Gray DL (2020): A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity. Int J Neuropsychopharmacol. 2020 May 27;23(5):287-299. doi: 10.1093/ijnp/pyaa007. PMID: 32055822; PMCID: PMC7251631.

  6. Arce, Balice-Gordon, Duvvuri, Naylor, Xie Z, Harel, Kozak, Gray DL, DeMartinis (2019):. A novel approach to evaluate the pharmacodynamics of a selective dopamine D1/D5 receptor partial agonist (PF-06412562) in patients with stable schizophrenia. J Psychopharmacol. 2019 Oct;33(10):1237-1247. doi: 10.1177/0269881119855302. PMID: 31264510.

  7. 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.

  8. 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.

  9. Riesenberg, Werth, Zhang Y, Duvvuri, Gray (2020): PF-06649751 efficacy and safety in early Parkinson’s disease: a randomized, placebo-controlled trial. Ther Adv Neurol Disord. 2020 Mar 6;13:1756286420911296. doi: 10.1177/1756286420911296. PMID: 32201505; PMCID: PMC7066585. n = 57 / 47