Dual 5-HT6 and D3 Receptor Antagonists in a Group of 1H-Pyrrolo[3,2-c]quinolines with Neuroprotective and Procognitive Activity

Grychowska, Katarzyna; Chaumont‐Dubel, Séverine; Kurczab, Rafał; Koczurkiewicz, Paulina; Deville, Caroline; Krawczyk, Martyna; Pietruś, Wojciech; Satała, Grzegorz; Buda, Szymon; Piska, Kamil; Drop, Marcin; Bantreil, Xavier; Lamaty, Frédéric; Pękala, Elżbieta; Bojarski, Andrzej J.; Popik, Piotr; Marin, Philippe; Zajdel, Paweł

doi:10.1021/acschemneuro.8b00618

Cited by 25 publications

(25 citation statements)

References 58 publications

(148 reference statements)

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“…Notably, intepirdine exhibited no glioprotective properties. 11 Similarly, although neuroprotective activity of selegiline was established in several in vitro models [45][46][47] , this irreversible MAO-B inhibitor did not reduce gliotoxicity induced by 6-OHDA in both cell-based assays ( Fig. 5A and 5B).…”

Section: Preliminary Evaluation Of Adme Propertiesmentioning

confidence: 86%

“…5,6 Several MTDLs have been reported, with the most prominent examples being dual enzymatic inhibition of acetylcholinesterase (AChE) and glycogen synthase kinase (GSK-3β), 7 inhibition of AChE and monoamine oxidase B (0) 8 and inhibition of β-secretase (BACE-1) and GSK-3β. 9 The MTDL strategy is further completed with GPCRs dual-acting compounds as 5-HT6/D3 and 5-HT2A/5-HT6 receptor antagonists [10][11][12][13] as well as 5-HT4R agonist/5-HT6R antagonist. 14 However, simultaneous targeting of enzyme and receptor activities constitutes a more challenging area.…”

Section: Introductionmentioning

confidence: 99%

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A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

Canale

Grychowska

Kurczab

et al. 2020

European Journal of Medicinal Chemistry

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The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking 5-HT6R scaffolds with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay and artificial membrane permeability, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.

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Section: Preliminary Evaluation Of Adme Propertiesmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

Canale

Grychowska

Kurczab

et al. 2020

European Journal of Medicinal Chemistry

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“…5-HT 6 R blockade has been proposed as a treatment of Alzheimer’s disease (AD) symptoms, however, the strategy ultimately failed, with no drugs on the market so far despite intensive clinical trial campaigns led by several companies [ 6 , 7 , 8 , 9 ]. Given the lack of efficacy of selective 5-HT 6 R antagonists in AD, several polypharmacological approaches have been proposed instead [ 10 , 11 , 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

Hogendorf

Kurczab

et al. 2021

Molecules

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A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.

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“…We show that the acute injection of SB258585, a 5-HT 6 receptor antagonist that behaves as inverse agonist [ 23 ], or of rapamycin, a mTOR inhibitor, abolishes deficits in long-term social and associative memories in Nf1 +/− mice and reduces mTOR overactivation in the PFC of these mice. Conversely, administration of ( S )-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1 H -pyrrolo [3,2-c]quinolone (CPPQ), a 5-HT 6 receptor neutral antagonist [ 21 , 33 , 34 ], does not induce any cognitive improvement, suggesting that mTOR under the control of constitutively active 5-HT 6 receptors, contributes to cognitive symptoms of NF1.…”

Section: Introductionmentioning

confidence: 99%

Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1

Doucet

Grychowska

Zajdel

et al. 2021

IJMS

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Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/− mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/− mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.

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Dual 5-HT₆ and D₃ Receptor Antagonists in a Group of 1H-Pyrrolo[3,2-c]quinolines with Neuroprotective and Procognitive Activity

Cited by 25 publications

References 58 publications

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1

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