2-Aminoimidazole-based antagonists of the 5-HT6 receptor – A new concept in aminergic GPCR ligand design

Hogendorf, Adam S.; Hogendorf, Agata; Kurczab, Rafał; Kalinowska‐Tłuścik, Justyna; Popik, Piotr; Nikiforuk, Agnieszka; Krawczyk, Martyna; Satała, Grzegorz; Lenda, Tomasz; Knutelska, Joanna; Bugno, Ryszard; Staroń, Jakub; Pietruś, Wojciech; Matłoka, Mikołaj; Dubiel, Krzysztof; Moszczyński-Pętkowski, Rafał; Pieczykolan, Jerzy; Wieczorek, Maciej; Pilarski, Bogusław; Zajdel, Paweł; Bojarski, Andrzej J.

doi:10.1016/j.ejmech.2019.06.001

Cited by 20 publications

(20 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Idalopirdine ( Figure 3A, magenta) represented an extended conformation, where fluoroalkyl chain lied in proximity to asparagine N2.63 (enabling the formation of a hydrogen-bond type of interaction) and aspartic acid D7.35 (in which it can form multipolar orthogonal type of interactions). SUVN-502 ( Figure 3B, green) shows a representative binding mode of 5-HT 6 antagonists [12,17,20], where the 2-Br substituted at the aryl ring was pointed (through the sp3 hybridization of sulfonamide linker) to a hydrophobic cavity formed by helixes 3-5. A slightly different way of interaction from Idalopiridine and SUVN-502 with the 5-HT 6 receptor showed KMP-10 ( Figure 3C One of the most commonly used screening methods of compound permeability is the testing of their passive penetration through the bilayer artificial membranes.…”

Section: Molecular Modelingmentioning

confidence: 99%

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

et al. 2019

Self Cite

View full text Add to dashboard Cite

Though the 5-HT6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT6R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT6R agents and insufficient “drugability.” Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT6R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and “druglikeness” characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT6R has been performed. “Druglikeness” was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats’ metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the “druglikeness” profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT6R.

show abstract

Section: Molecular Modelingmentioning

confidence: 99%

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…[21][22][23][24] Pharmacological blockade of 5-HT6R, located on GABA-ergic and glutamatergic neurons, increases cholinergic transmission. 25,26 Consequently, 5-HT6R antagonists show beneficial effects on cognition, as shown by a various preclinical studies and preliminary clinical studies [27][28][29] that revealed pro-cognitive effects in humans. 30 However, phase III clinical trials for these compounds showed disappointing results.…”

Section: Introductionmentioning

confidence: 94%

“…to obtain intermediates 9-13. The same procedure was employed for the alkylation 4-hydroxybenzaldehyde with different di-bromoalkane to achieve intermediates 14General procedure for the alkylation of N1-functionalized-4-indol-piperazine(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) 1-(3-Chlorobenzyl)-4-(piperazin-1-yl)-1H-indole 5 (150 mg, 0.46 mmol 1 eq) and freshly grinded K2CO3 (190 mg 1.38 mmol, 3 eq) were suspended in 5 ml of acetone, followed by the dropwise addition of the corresponding alkylating agent 9-17 (0.55 mmol, 1.2 eq). The reaction mixture was stirred at 60 °C overnight.…”

mentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…In 2019 Hogendorf et al [90] published a comprehensive SAR study involving more than 50 compounds, all containing an aminoimidazole moiety as a new bioisoster of the classical PI amino-group. These were found to form strong hydrogen bonds with electronegative acceptors, such as carbonyls, in the enzyme active site.…”

Section: Antagonists For 5-ht6rmentioning

confidence: 99%

Small Molecule Drugs for Treatment of Alzheimer’s Diseases Developed on the Basis of Mechanistic Understanding of the Serotonin Receptors 4 and 6

Jansen¹,

Qvortrup²

2022

Serotonin and the CNS - New Developments in Pharmacology and Therapeutics

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common form of dementia affecting millions of people worldwide and currently, the only possible treatment is the use of symptomatic drugs. Therefore, there is a need for new and disease-modifying approaches. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of serotonin receptors the subtype 4 and 6 receptors (5-HT4R and 5-HT6R) has received increasing attention and has become a promising target for improving cognition and limit the amyloid pathology through modulation of the neurotransmitter system. A large number of publications describing the development of ligands for these serotonin receptors have emerged, and their pharmaceutical potential is now quite evident. However, 5-HT4R and 5-HT6R functionality is much more complex than initially defined. This chapter describes recent advances in the understanding of this modulation as well as the medicinal chemistry efforts towards development of selective 5-HT4R or 5-HT6R ligands.

show abstract

2-Aminoimidazole-based antagonists of the 5-HT6 receptor – A new concept in aminergic GPCR ligand design

Cited by 20 publications

References 44 publications

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

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

Small Molecule Drugs for Treatment of Alzheimer’s Diseases Developed on the Basis of Mechanistic Understanding of the Serotonin Receptors 4 and 6

Contact Info

Product

Resources

About