Chemical manipulations on the 1,4-dioxane ring of 5-HT1A receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells

Bello, Fabio Del; Bonifazi, Alessandro; Giorgioni, Gianfabio; Quaglia, Wilma; Amantini, Consuelo; Morelli, Maria Beatrice; Santoni, Giorgio; Battiti, Francisco O.; Vistoli, Giulio; Cilia, Antonio; Piergentili, Alessandro

doi:10.1016/j.ejmech.2019.02.056

Cited by 14 publications

(9 citation statements)

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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%

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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“…5-HT is a potent mitogen for many types of nontumoral cells [ 120 , 121 ] as well as for tumor cells from the lung, pancreas, colon, bladder, and prostate [ 122 , 123 , 124 , 125 , 126 ]. However, the serotonin-induced signaling pathways in cancer are complex and only partially understood (reviewed in [ 127 ]).…”

Section: Molecules With a Widespread Activity In Various Types Of Can...mentioning

confidence: 99%

An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation

Arese

Bussolino

Pergolizzi

et al. 2022

IJMS

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We propose an overview of the molecular cues and their intracellular signaling involved in the crosstalk between cancer and the nervous system. While “cancer neuroscience” as a field is still in its infancy, the relation between cancer and the nervous system has been known for a long time, and a huge body of experimental data provides evidence that tumor–nervous system connections are widespread. They encompass different mechanisms at different tumor progression steps, are multifaceted, and display some intriguing analogies with the nervous system’s physiological processes. Overall, we can say that many of the paradigmatic “hallmarks of cancer” depicted by Weinberg and Hanahan are affected by the nervous system in a variety of manners.

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“…Over the last decade, we have demonstrated that the 1,4-dioxane nucleus represents a bioversatile carrier of ligands interacting with different receptor systems, − including D 2 -like receptors . In particular, two properly substituted 1,4-dioxane compounds endowed with the fruitful multitarget combination of 5-HT 1A R/D 4 R agonism and D 2 R/D 3 R/5-HT 2A R antagonism (compound 1 ) or D 2 R/D 3 R/D 4 R/5-HT 1A R agonism (compound 2 ) have been discovered as potential starting points to develop new pharmacological tools for schizophrenia and PD therapy, respectively (Figure ).…”

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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Chemical manipulations on the 1,4-dioxane ring of 5-HT1A receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells

Cited by 14 publications

References 48 publications

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

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

An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation

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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Chemical manipulations on the 1,4-dioxane ring of 5-HT1A receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells

Cited by 14 publications

References 48 publications

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

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

An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation

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