Objective: The objective was to characterize novel dopamine D1PAMs pre-clinically in behavioral and neurochemical models and in phase 1 human studies in healthy volunteers and Parkinson’s disease (PD) subjects.

Background: The dopamine (DA) D1 receptor is important for higher cognitive functions, wakefulness, motor activity and reward. Positive allosteric modulation of the DA D1 receptor (D1PAM) is a novel mechanism that could avoid problems associated with DA D1 agonists such as, poor drug like properties,  inverted U-shaped dose response and rapid tolerance development.  The D1PAM,  LY3154207, is currently in phase 2 testing in Lewy Body Dementia (PRESENCE, NCT02603861)

Method: Recently discovered selective D1PAMs (DETQ, DPTQ and LY3154207) were tested in vitro in cell lines expressing the hD1 receptor and in vivo using the humanized D1 (hD1) mouse and also in rhesus monkeys.  Single and multiple ascending doses of LY3154207 was evaluated for safety/tolerability and pharmacokinetics (PK) in healthy volunteers and PD subjects. A biomarker study in healthy subjects assessed effects on wakefulness using the Multiple Sleep Latency Test after 24 hours sleep deprivation.

Results: The D1PAMs showed low nM potency in vitro with an EC50 of 3 nM for LY3154207 in the hD1 cAMP assay and high selectivity vs other targets. Increased locomotion was seen (3-240 mg/kg, PO) in the hD1 mouse without inverted U-shaped dose response curves or tolerance development. In vivo neurochemical studies showed increased release of acetylcholine and histamine in cortical areas. DETQ restored deficits in novel object recognition in aged (16-22 months) hD1 mice and DETQ also reversed hypo-locomotion in hD1 mice with partial DA depletions.  In the rhesus monkey, DPTQ (0.1 -2.5 mg/kg, IM) showed sustained improvements in spatial working memory performance. Phase 1 clinical studies with LY3154207 demonstrated an acceptable safety and linear plasma PK profiles and CSF PK data showed relevant central exposures. LY3154207 improved wakefulness in sleep deprived subjects and showed a signal for efficacy on motor symptoms in PD subjects.

Conclusion: The current data provide support for the use of D1PAM in the treatment of several neuropsychiatric disorders. The preclinical results suggest different profiles when compared to D1 agonists that could offer therapeutic advantages.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preclinical-pharmacology-and-early-clinical-development-of-dopamine-d1-positive-allosteric-modulators-d1pams-with-therapeutic-potential-for-neuropsychiatric-disorders/