Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders

Abstract

DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.

The interactions of dopamine and oxidative damage in the striatum of patients with neurodegenerative diseases

“…Amongst dopamine receptors, the D1R variety are crucially implicated in maintaining higher cognitive functions – in particular working memory, attention, and executive functions (Bruns et al ). The increases in D1R density in striatum of patients with LBD can in all likelihood be explained by the fact that dopamine receptor function is strongly associated with the compensatory mechanism to make up for the loss of excitatory D1R stimulation (Perez et al ).…”

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…The DA binding site is contained in a membrane pocket formed by the TM3/5/6/7 with similarities across biogenic amines GPCRs. Molecular docking studies for the D1 receptor were able to demonstrate the presence of allosteric sites that were further targeted to obtain highly selective positive allosteric modulators with high potency, weak agonist properties and able to increase DA response (cAMP) ( Bruns et al., 2018 ). The mode of interaction of biased agonists is different since they fail to trigger D1 receptor desensitization in vitro .…”

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

“…While orthosteric D 1 agonists have the disadvantage of having a narrow therapeutic window, positive allosteric modulators could fulfill the task to give an optimal prefrontal D 1 receptor activation. In accordance with this conjecture, a dopamine D 1 receptor-positive allosteric modulator, namely, dichlorophenylacetyl 5-(1-hydroxy-1-methyl-ethyl) tetrahydroisoquinoline (DETQ), demonstrated the potential efficacy of D 1 potentiators for the treatment of cognitive deficits and negative symptoms in schizophrenia [ 124 ].…”