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. PF-3628
• 3. CY208,243
• 4. Tavapadon (PF-06649751)

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