Parkinson’s disease (PD) is a neurodegenerative disorder that manifests clinically through motor symptoms like resting tremor, bradykinesia, muscle stiffness, and impaired gait. It also presents non-motor symptoms, including cognitive decline, depression, constipation, and disrupted sleep [1], [2], [3]. The pathological hallmarks of PD encompass extensive dopaminergic neuron death (over 50 %) in the substantia nigra pars compacta, widespread degeneration of pigmented neurons, a marked decrease (more than 80 %) in striatal dopamine levels, abnormal α-synuclein aggregation, and Lewy bodies within the cytoplasm of surviving substantia nigra neurons [4], [5], [6], [7].

Dopaminergic neurons regulate essential physiological functions such as behavior, cognition, movement, and the neuroendocrine response [8]. The progressive loss of dopaminergic neurons leads to a depletion of dopamine in the striatum, a primary contributor to PD’s motor symptoms [9]. Considering dopamine’s critical role in alleviating PD motor symptoms, clinicians use dopamine supplementation therapy to enhance dopamine levels in the CNS by targeting specific aspects of its biosynthesis, transport, metabolism, or receptor function [10]. The therapy primarily utilizes drugs such as levodopa [11], [12], dopamine receptor agonist [13], [14], monoamine oxidase B (MAO-B) inhibitors [15], [16], catechol-O-methyltransferase inhibitors (COMT) [17], [18] and adenosine A2 receptor antagonists [19], [20].

COMT and MAO are the main enzymes responsible for dopamine metabolism. COMT can methylate dopamine into 3-methoxytyramine (3-MT), while MAO can oxidize and deaminate dopamine into 3,4-dihydroxyphenylacetaldehyde (DOPAA), resulting in the production of ammonia and hydrogen peroxide [21], [22]. Dopamine is ultimately metabolized into homovanillic acid (HVA), with the involvement of enzymes like acetaldehyde dehydrogenase (ALDH) and aromatic l-amino acid decarboxylase (AADC) (Fig. 1). Additionally, levodopa can also undergo metabolism by COMT, resulting in the formation of the inactive 3-O-Methyldopa (3-OMD). Taking into account the involvement of COMT and MAO-B in the metabolism of dopamine and levodopa, the development of COMT/MAO dual inhibitors to hinder dopamine metabolism pathways could potentially lead to synergistic effects and benefits, such as delaying drug resistance and improving effectiveness [23], [24].

Herein, we present the results of the chemical optimization and pharmacological evaluation of a new COMT inhibitor that also has mild MAO-B inhibitory effects. We conducted a comprehensive investigation into the binding mode between ligands and proteins, incorporating pharmacophore elements from FDA-approved COMT inhibitors (Entacapone, tolcapone) and MAO-B inhibitors (Selegiline, rasagiline, safinamide) based on a pharmacophore fusion strategy. We have identified a series of new nitrocatechol analogs that exhibit potent inhibitory activity against COMT, capable of alleviating dopamine deficit induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).