Objective: To characterize the in vitro and in vivo pharmacologic profile of UCB0022
Background: Parkinson’s disease (PD) is a progressive neurodegenerative disease with reductions in dopamine levels throughout the brain associated with multiple motor and non-motor symptoms. Although dopamine-replacement therapies such as levodopa are initially effective, chronic use is associated with declining efficacy and clinically relevant complications of therapy for patients, such as motor fluctuations and dyskinesia. Orthosteric dopamine 1 (D1) receptor (D1R) agonists have limited utility due to eg poor bioavailability. Recent efforts have been made to find novel ways to modulate D1Rs in people with PD. UCB0022 is an orally available, brain-penetrant small molecule and the result of a program aimed at discovering selective D1 positive allosteric modulators (D1 PAMs).
Method: Cell-based functional and binding assays were used to determine the affinity, allosteric efficacy and selectivity of UCB0022. In vivo proof-of-pharmacology was obtained in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques (cynomolgus monkey), a recognized model of the PD phenotype.
Results: In vitro, UCB0022 selectively bound D1Rs with nanomolar affinity and enhanced the potency of dopamine to activate D1Rs by approximately 10-fold. UCB0022 was inactive at D2, D3 and D4 receptors and marginally active at D5 dopamine receptors at 10 µM. UCB0022 was also highly selective towards a broad range (>500) of secondary targets. In MPTP-treated macaques, UCB0022 (single oral doses, alone or in combination with a low dose of levodopa) improved motor disability similar to levodopa but with reduced dyskinesia. Preclinical pharmacokinetic (PK) and safety data support continued development of UCB0022.
Conclusion: UCB0022 is a selective and potent D1 PAM, able to improve motor disability in MPTP-treated macaques as effectively as levodopa, but with a reduction in severe dyskinesia. Together with favorable PK and safety profiles, these data supported the progression of UCB0022 to first-in-human studies.
To cite this abstract in AMA style:
C. Vermeiren, A. Ates, F. Bouzom, A. Delaunois, M. Gillard, B. Kenda, A. Ousset, L. Provins, D. Skolc, A. Valade, M. Vanmeulder, M. Wood, Y. Lamberty. Preclinical characterization of UCB0022, an oral, brain penetrant, selective, clinical-stage positive allosteric modulator of the dopamine 1 receptor (D1 PAM) [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/preclinical-characterization-of-ucb0022-an-oral-brain-penetrant-selective-clinical-stage-positive-allosteric-modulator-of-the-dopamine-1-receptor-d1-pam/. Accessed May 18, 2025.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/preclinical-characterization-of-ucb0022-an-oral-brain-penetrant-selective-clinical-stage-positive-allosteric-modulator-of-the-dopamine-1-receptor-d1-pam/