Multitarget 1,4-Dioxane Compounds Combining Favorable D<sub>2</sub>-like and 5-HT<sub>1A</sub> Receptor Interactions with Potential for the Treatment of Parkinson’s Disease or Schizophrenia

Bello, Fabio Del; Ambrosini, Dario; Bonifazi, Alessandro; Newman, Amy Hauck; Keck, Thomas M.; Giannella, Maddalena; Giorgioni, Gianfabio; Piergentili, Alessandro; Cappellacci, Loredana; Cilia, Antonio; Franchini, Silvia; Quaglia, Wilma

doi:10.1021/acschemneuro.8b00677

Cited by 15 publications

(21 citation statements)

References 34 publications

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“…To overcome the major limitations of a single-medication therapy, design and discovery of multi-target compounds emerge as a possible alternative strategy for PD [26]. Pardoprunox (SLV-308), which is agonist of D 2 /D 3 receptors and full agonist of 5-HT 1A receptor, reached the phase III clinical trial for the treatment of early stage PD with low side effects, like psychosis or dyskinesia [7].…”

Section: Discussionmentioning

confidence: 99%

“…The D 2 -like D 2 R, D 3 R, and D 4 R stimulate G a i/o to inhibit adenylate cyclase activity and cyclic adenosine monophosphate (cAMP) production. Full or partial D 2 R and D 3 R agonists are widely used in PD therapy, whereas D 2 R/D 3 R antagonists are effective in treatment of schizophrenia [7]. D 4 R, mainly expressed in the hippocampus and prefrontal cortex, affects exploratory behavior, attention, and inhibitory avoidance tasks.…”

Section: Introductionmentioning

confidence: 99%

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Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

et al. 2019

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Modulation of multiple protein targets with a single compound is essential for the effective treatment of central nervous system disorders. In our previous G protein-coupled receptor (GPCR) cell-based study, a selective human monoamine oxidase (hMAO)-A inhibitor, eckol, stimulated activity of dopamine D3 and D4 receptors. This result led to our interest in marine phlorotannin-mediated modulation of hMAO enzymes and related GPCRs in neuronal disorders. Here, we evaluate the multi-target effects of phloroglucinol, phlorofucofuroeckol-A (PFF-A), and dieckol by screening their modulatory activity against hMAO-A and -B and various neuronal GPCRs. Among the tested phlorotannins, PFF-A showed the strongest inhibitory activity against both hMAO isoforms, with higher selectivity toward hMAO-B than hMAO-A. Enzyme kinetics and docking data revealed that PFF-A noncompetitively acts on hMAOs into the alternative binding pocket of enzymes with allosteric functions. In a functional assay for GPCR screening, dieckol and PFF-A exhibited a multi-target combination of D3R/D4R agonism and D1/5HT1A/NK1 antagonism. In particular, they effectively stimulated D3R and D4R, compared to other GPCRs. Docking analysis confirmed that dieckol and PFF-A successfully docked into the conserved active sites of D3R and D4R and interacted with aspartyl and serine residues in the orthosteric binding pockets of the respective receptors. Based on our experimental and computational data, we established the structure-activity relationship between tested phlorotannins and target proteins, including hMAOs and GPCRs. Our current findings suggest that hMAO inhibitors dieckol and PFF-A, major phlorotannins of edible brown algae with multi-action on GPCRs, are potential agents for treatment of psychological disorders and Parkinson’s disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

et al. 2019

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“…The 1,4-dioxane nucleus has been demonstrated to be a versatile scaffold for the development of compounds interacting with different receptor systems, − including mAChRs. − We have demonstrated that the size of the substituent in the 6-position affects the functional activity of 1,4-dioxane ligands directed to mAChRs . Indeed, a methyl group in this position led to the effective agonist (2 R ,6 S )- 1 , whereas aromatic rings characterized potent antagonists, such as the 6,6-diphenyl derivative ( S )- 2 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

et al. 2020

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A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M 1 –M 5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b , with a cis configuration between the CH 2 N + (CH 3 ) 3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed p K i values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2 S ,6 S )-(−)- 3b and (2 S ,6 S )-(−)- 33b , respectively. Docking simulations on the M 3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood–brain barrier, and the high M 3 /M 2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M 3 receptors are involved.

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Section: Introductionmentioning

confidence: 99%

Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D₃ Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders

Bonifazi

Newman

Keck

et al. 2021

ACS Chem. Neurosci.

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In the search for novel bitopic compounds targeting the dopamine D 3 receptor (D 3 R), the N -(2,3-dichlorophenyl)piperazine nucleus (primary pharmacophore) has been linked to the 6,6- or 5,5-diphenyl-1,4-dioxane-2-carboxamide or the 1,4-benzodioxane-2-carboxamide scaffold (secondary pharmacophore) by an unsubstituted or 3-F-/3-OH-substituted butyl chain. This scaffold hybridization strategy led to the discovery of potent D 3 R-selective or multitarget ligands potentially useful for central nervous system disorders. In particular, the 6,6-diphenyl-1,4-dioxane derivative 3 showed a D 3 R-preferential profile, while an interesting multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9 , respectively, which displayed potent D 2 R antagonism, 5-HT 1A R and D 4 R agonism, as well as potent D 3 R partial agonism. They also behaved as low-potency 5-HT 2A R antagonists and 5-HT 2C R partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents.

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Multitarget 1,4-Dioxane Compounds Combining Favorable D₂-like and 5-HT_1A Receptor Interactions with Potential for the Treatment of Parkinson’s Disease or Schizophrenia

Cited by 15 publications

References 34 publications

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D₃ Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders

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Multitarget 1,4-Dioxane Compounds Combining Favorable D2-like and 5-HT1A Receptor Interactions with Potential for the Treatment of Parkinson’s Disease or Schizophrenia

Cited by 15 publications

References 34 publications

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D3 Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders

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Multitarget 1,4-Dioxane Compounds Combining Favorable D₂-like and 5-HT_1A Receptor Interactions with Potential for the Treatment of Parkinson’s Disease or Schizophrenia

Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D₃ Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders