Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7–11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5–40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM).

Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

“…The discovery of heteromeric receptors has led to a new interest in the development of mixed action drugs for combination therapies, or drugs which selectively bind to receptor heteromers [ 138 , 387 ]. A heterobivalent ligand combining D 2 R agonism with A 2A R antagonism could be an effective antiparkinsonian drug and might also be radiolabeled for PET imaging of A 2A R/D 2 R heteromers [ 388 ]. The potential of such mixed-actions drugs has been demonstrated in the opioid system, where successful bivalent analgesics combining µ-agonism with δ-antagonism have been developed [ 389 , 390 ].…”

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

“…In particular, interest was considered to substituted pyrimidines promising for the treatment of neurological diseases [32,33]. The therapeutic effect of a variety of 2,4,5-and 2,4,6-trisubstituted pyrimidines is mainly attributed to an antagonistic effect to the adenosine receptors A 1 [34,35] and A 2A [36,37]. The findings regarding the A 2A receptor signaling in pain have been controversial, with studies supporting both pro-and antinociceptive roles.…”

Artificial intelligence and machine learning‐aided drug discovery in central nervous system diseases: State‐of‐the‐arts and future directions

“…On the contrary, recently, AI/ML has received little attention in PD drug discovery. Particularly, Shao et al 403 initially built SVM models to quickly select the compounds containing indole–piperazine–pyrimidine scaffold among large chemical databases and subsequently identified novel compounds that simultaneously bind the two receptors—adenosine A2A receptor and dopamine D2 receptor—implicated in the PD pathophysiology. In another study, Sebastián‐Pérez 404 utilized several ML techniques to infer QSAR models for the identification of putative inhibitors of LRRK2 protein, a key genetic risk factor for familiar and sporadic PD.…”