Objective: Introduce the mechanism of action for dopamine D1 positive allosteric modulator (D1PAM) as a new target for neuropsychiatric disorders. Describe the preclinical profile of lead D1PAMs including DETQ, DPTQ and LY3154207. The latter compound is currently in phase 2 for Lewy Body Dementia (LBD).

Background: Dopamine D1 receptors play a key role in higher cognitive functions, motor activity and mood/reward. A D1PAM may address issues associated with D1 agonists including poor drug like properties, inverted U-shaped dose response and tolerance development.

Method: In vitro potency and efficacy in the cAMP assay was performed using human D1 cells. In vivo testing was done in human D1 receptor knock-in (hD1KI) mice due to a species differences in D1PAM binding. Central D1 receptor mediated effects were also studied in the rhesus monkey using the spontaneous eye blink rate and spatial working memory models. All studies used systemic administration of D1PAMs

Results: LY3154207 is a potent D1PAM in vitro (cAMP EC50 of 3.7 nM) with 14-fold alpha-shift. In vivo motor activity in hD1KI mice was increased over a wide dose range (3-240 mg/kg, PO) without evidence for inverted U-shaped dose-response, rapid tolerance development or disruption of spontaneous alteration in the Y-maze, which is in contrast to D1 agonists. LY3154207 also reversed hypo-activity caused by pre-treatment with a low dose of the dopamine depleting agent reserpine (an animal model for motor symptoms in Parkinson’s disease). In vivo microdialysis studies revealed increased release in acetylcholine in the hippocampus and the PFC and sleep EEG studies showed dose related wake promoting effects. LY3154207 also increased brain phosphorylation of CREB and GluR1, both markers of synaptic plasticity. In the rhesus monkey, LY3154207 and the close structural analog DPTQ increased spontaneous eye blink rate, effects were blocked by a D1 receptor antagonist. Acute dosing with DPTQ (0.1-2.5 mgkg, IM) enhanced spatial working memory performance in the adult rhesus monkey. Depending on the dose, the enhanced performance was observed at 48 or 72 hours post dosing and sustained for up to 14 days.

Conclusion: Preclinical data for D1PAM’s, including LY3154207, support the potential utility of this new mechanism in the treatment of several neuropsychiatric disorders including LBD and Alzheimer’s disease. Part of the data presented at the ADPD meeting, March 2019.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preclinical-profile-of-dopamine-d1pam-a-novel-mechanism-in-clinical-development-for-lewy-body-dementia/