Novel non-sulfonamide 5-HT 6 receptor partial inverse agonist in a group of imidazo[4,5- b ]pyridines with cognition enhancing properties

Vanda, David; Soural, Miroslav; Canale, Vittorio; Chaumont‐Dubel, Séverine; Satała, Grzegorz; Kos, Tomasz; Funk, Petr; Fülöpová, Veronika; Lemrová, Barbora; Koczurkiewicz, Paulina; Pękala, Elżbieta; Bojarski, Andrzej J.; Popik, Piotr; Marin, Philippe; Zajdel, Paweł

doi:10.1016/j.ejmech.2017.12.053

Cited by 40 publications

(44 citation statements)

References 29 publications

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“…In vitro biotransformation assays of selected compounds 9 and 10 were performed using rat-liver microsomes (RLM), potassium-phosphate buffer, NADPH-regenerating system (NADP, glucose-6-phosphate, glucose-6-phosphate dehydrogenase), and levallorphan as internal standard, according to the previously published procedure [ 27 ]. Compound I and the drug tamsulosin were used as reference standard.…”

Section: In Vitro Experimentsmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile

et al. 2018

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Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α1A-/α1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α1-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro-N-([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α1A-/α1D-adrenoceptor antagonist (Ki(α1) = 50 nM, EC50(α1A) = 0.8 nM, EC50(α1D) = 1.1 nM), displayed selectivity over α2-adrenoceptors (Ki(α2) = 858 nM), and a 5-fold functional preference over the α1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Clint = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.

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Section: In Vitro Experimentsmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile

et al. 2018

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“…DHβE was administered at a dose that has been previously demonstrated to block the procognitive effects of TC-2403 [25,27]. The doses of ketamine and scopolamine, adopted from our published protocols [28,30], have been demonstrated to produce reliable impairment using the NORT.…”

Section: Drug Administrationmentioning

confidence: 99%

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

et al. 2020

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Rationale The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4β2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized. Objectives The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM. Methods Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats. Results The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-β-erythroidine, a relatively selective α4β2-nAChR antagonist, indicating the involvement of α4β2-nAChRs in cognitive processes. The tested α4β2-PAM was also effective against ketamine-and scopolamine-induced deficits of object recognition memory. Moreover, procognitive effects were also observed after combined treatment with inactive doses of dFBr and TC-2403, a selective α4β2-nAChR agonist. Conclusions These findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.

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“…Paradoxically, 5-HT 6 receptor agonists have similar cognitive effects to antagonists of the same receptor, so prolong NOD memory in normal animals [129] and reverse a variety of acute NMDA receptor antagonist-induced NOD deficits [130,131,132]. The underlying neurochemical mechanisms remain unclear, since 5-HT 6 agonists actually facilitate GABAergic and inhibit glutamatergic neurotransmission in the hippocampus and cortex [53,55,82,133].…”

Section: Discussionmentioning

confidence: 99%

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

et al. 2020

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Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates "dual-hit" neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal-and drugevoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT 6 antagonistevoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT 6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu 7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT 6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT 6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT 6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu 7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics.

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Novel non-sulfonamide 5-HT 6 receptor partial inverse agonist in a group of imidazo[4,5- b ]pyridines with cognition enhancing properties

Cited by 40 publications

References 29 publications

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

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