Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Abstract

Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

“…A single drug targeting more than 1 protective pathway, such as AM6701, provides a unique approach related to the use of combinatorial treatments for different neurodegenerative diseases. For example, the use of inhibitor cocktails in studies of Parkinson's disease [68,69], Alzheimer's disease [70][71][72], and stroke [73,74] appears effective for therapeutic intervention. The additive or synergistic efficacy of a compound such as AM6701 may also help alleviate adverse drug effects by reducing the number of administered agents to target different pathways for precise fine-tuning of cannabinergic signaling.…”

The use of multi-target drugs in the treatment of neurodegenerative diseases

“…Caffeine, in fact, has been suggested to protect against Ab neurotoxicity [49], while acute treatment with caffeine and the A 2A receptor antagonist ZM241385 was found to reverse age-related olfactory deficits and memory decline in rats [50], clearly suggesting involvement of A 2A , and not A 1 , receptors in cognitive decline and, possibly, neurodegenerative processes. Evidence such as this, and other evidence for neuroprotection also in parkinsonian models, led to the evaluation of (E)-8-styryl-xanthinyl-derived adenosine A 2A receptor antagonists also for inhibition of MAO-B in several studies (reviewed in [51]). All of the compounds tested demonstrated MAO-B inhibition in the low micromolar to high nanomolar range, suggesting that the neuroprotective properties of known adenosine A 2A receptor antagonists may be in part due to MAO-B inhibition, in synergism with their A 2A antagonism [51].…”

“…Evidence such as this, and other evidence for neuroprotection also in parkinsonian models, led to the evaluation of (E)-8-styryl-xanthinyl-derived adenosine A 2A receptor antagonists also for inhibition of MAO-B in several studies (reviewed in [51]). All of the compounds tested demonstrated MAO-B inhibition in the low micromolar to high nanomolar range, suggesting that the neuroprotective properties of known adenosine A 2A receptor antagonists may be in part due to MAO-B inhibition, in synergism with their A 2A antagonism [51].…”

Dual inhibition: a novel promising pharmacological approach for different disease conditions

“…Dual monoamine oxidase B inhibitors and adenosine A2A receptor antagonists Methylxanthines [26] and (E,E)-8-(4-phenylbutadien-1-yl)caffeine [27] Inflammation Dual cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) inhibitors Flavocoxid [28] and ML3000 (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-H-pyrrolizine-5-yl) acetic acid [29] Hypertension Dual inhibitors of neprilysin and angiotensin-converting enzyme BMS-182657, [30] MDL-100173 [31] and S21402 (RB105) {N-[2S,3R-(2-mercaptomethyl-1-oxo-3-phenylbutyl)-l-alanine]} [32] Dual inhibitors of the angiotensin II receptor and neprilysin LCZ696 [33] Dual inhibitors of angiotensin-converting and endothelin-converting enzymes CGS 26303 [34] and SLV 306 (Daglutril) [35] Dual vasopressin receptor (V1/V2) antagonists (RWJ-676070) [36] Thrombosis Dual-acting anticoagulant/antiplatelet inhibitors MC45301, MC45308, MC45350, and MC45403 derived from vitamin B6 (pyridoxine) [37] Microbial infections Dual inhibitors of type I and type II DNA topoisomerases Some novel indolyl quinoline analogs [38] Dual inhibitors of b-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) Platencin [39] Viral infections Dual inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H Madurahydroxylactone derivatives [40] Dual inhibitors of 2A and 3C proteases encoded by human rhinoviruses (HRVs) LY343814 [41] Cancer Dual PI3K and mTOR inhibitors PI-103, [42] NVP-BEZ235, [43] WJD008 [44] and BAG956 [45] Dual topoisomerases I and II inhibitors Benzophenanthridine alkaloids, indolocarbazoles and lipophilic bis(naphthalimides), anthraquinones, pyridoindoles, indenoquinolones, acridines, TAS-103, leptosins (Leps) F and C, tafluposide (F 11782) and XR11576 [46][47][48][49][50] Dual inhibitors of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 NVP-AEE788 [51] Dual inhibitors of IkappaB kinase-2 (IKK2) and Fms-like tyrosine kinase 3 (FLT3) AS602868 [52] The new hybrids retain the potent and selective human AChEinhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in-vitr...…”

“…A number of methylxanthines exhibiting such dual action are being optimized. [26] Moreover (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues are also considered promising candidates in the class of dual-acting compounds (Figure 1n). [27] …”