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The serotonin type 6 receptor (5-HT 6 R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT 6 R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT 6 R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT 6 R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT 6 R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT 6 R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT 6 R and provide insight into the glioprotective properties of 5-HT 6 R neutral antagonists at Gs signaling., Competing Interests: Declaration of competing interest All authors disclose no financial or personal relationships that may be perceived as influencing their work., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT 6 R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HT 6 R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT 6 R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT 6 R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Serotonin type 6 receptor (5-HT 6 R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1 H -pyrrolo[3,2- c ]quinoline scaffold to provide the 2-phenyl-1 H -pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT 6 R. This modification has changed the compound's activity at 5-HT 6 R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT 6 R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1 H -pyrrole-3-carboxamide might be used as a template for designing 5-HT 6 R inverse agonists.

Modulators of the serotonin 5-HT6 receptor (5-HT6R) offer a promising strategy for the treatment of the cognitive deficits that are associated with dementia and Alzheimer's disease. Herein, we report the design, synthesis, and characterization of a novel class of 5-HT6R antagonists that is based on the 1H-pyrrolo[3,2-c]quinoline core. The most active compounds exhibited comparable binding affinity to the reference compound, SB-742457, and markedly improved selectivity. Lead optimization led to the identification of (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (14) (Ki = 3 nM and Kb = 0.41 nM). Pharmacological characterization of the 5-HT6R's constitutive activity at Gs signaling revealed that 14 behaved as a neutral antagonist, while SB-742457 was classified as an inverse agonist. Both compounds 14 and SB-742457 reversed phencyclidine-induced memory deficits and displayed distinct procognitive properties in cognitively unimpaired animals (3 mg/kg) in NOR tasks. Compounds 14 and SB-742457 were also active in the Vogel test, yet the anxiolytic effect of 14 was 2-fold higher (MED = 3 mg/kg). Moreover, 14 produced, in a 3-fold higher dose (MED = 10 mg/kg), antidepressant-like effects that were similar to those produced by SB-742457 (MED = 3 mg/kg). Together, these data suggest that the 4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline scaffold is an attractive molecular framework for the development of procognitive agents. The results are promising enough to warrant further detailed mechanistic studies on the therapeutic potential of 5-HT6R antagonists and inverse agonists for the treatment of cognitive decline and depression/anxiety symptoms that are comorbidities of Alzheimer's disease.

The unprecedented eco-friendly Pt-catalyzed 5-endo-dig cycloisomerization of readily available α-amino ynones is reported under microwave irradiation in PEG-3400 as reaction matrix. The corresponding pure pyrrolin-4-ones were obtained in excellent yields (80-98%) directly after a straightforward precipitation-filtration workup, thus avoiding any chromatographic purification. The catalytic system was recycled and the chiral purity of all the products was also investigated.

2,5-Dihydro-1H-pyrrole-3-carboxylates are important building blocks for the synthesis of high value pyrroles and pyrroloquinoline derivatives with interesting biological activities. The use of continuous flow allowed us to perform a key synthetic step, namely ruthenium-catalyzed ring-closing metathesis, with a residence time of 1 min at 120 °C. Dimethyl carbonate, a green solvent, was demonstrated for the first time to be an excellent solvent for this reaction in continuous flow. The continuous flow conditions proved to be general and the scale-up of this reaction was not only possible, but also highly efficient. Conversion of 10 grams of diene was realized in 37 minutes under continuous flow, yielding the desired heterocycle in 91% yield. [ABSTRACT FROM AUTHOR]

The rapid and facile synthesis of highly substituted β-iodofurans and β-iodopyrroles is reported using a mixture of molecular iodine and a base in solid PEG 3400 as alternative, eco-friendly and nontoxic solvent under microwave irradiation, in a very short time. The heterocycles are efficiently recovered in good yields by a simple workup procedure, avoiding chromatographic purification [ABSTRACT FROM AUTHOR]

Cross-coupling reaction of alkyl and aryl magnesium halides with 4-chloro-pyrrolo-[3,2-c]quinoline in the presence of a catalytic amount of iron salt is described. The reactions are completed in 30 min, resulting in moderate to excellent yields of 52-94% in a tetrahydrofuran (THF)-N-methylpyrrolidinone (NMP) solvent mixture. [ABSTRACT FROM AUTHOR]

Ring-closing metathesis (RCM) is a powerful tool for the preparation of cyclic organic compounds. Yet, one of the major limitations of this method is the difficulty to prepare large quantities of target molecules. Herein we describe a comprehensive study regarding the gram-scale synthesis of 2-aryl-1 H -pyrrole-3-carboxylates based on the ring-closing metathesis of the corresponding β-amino esters as a key step. This study includes evaluation of solvent and catalyst as well as reaction kinetics on the RCM. After an aromatization step, this methodology allowed for an efficient generation of variously substituted and unprecedented 2-aryl-1 H -pyrrole-3-carboxylates in good yields and cost-effectiveness. The resulting molecules might serve as key building blocks for the generation of CNS-oriented compound libraries. [ABSTRACT FROM AUTHOR]

The 2-trimethylsilylethanesulfonyl (or SES) protecting group was compared to the tosyl (Ts) group in the preparation of a nitrogen-containing five-membered ring obtained by the aza-Baylis—Hillman/alkylationlRCM route. While deprotection of Ts-protected pyrrolines gave only pyrroles, deprotection of the same SES-protected compounds gave either pyrroles or free amine pyrrolines depending on the deprotection conditions. The SES-protected pyrrolines were hydrogenated to yield pyrrolidines with an excellent diastere-oselectivity. Free amine pyrrolidines were obtained by HF-mediated deprotection of the SES group. [ABSTRACT FROM AUTHOR]

A new route to diverse 2-substituted-3-methoxycarbonyl pyrroles has been developed. Diverse SES protected α-methylene β-aminoesters were obtained by a 3-component aza-Baylis-Hillman reaction. Diversity arose from the aryl aldehydes which can be used in this reaction. N-Alkylation with allyl bromide under mild conditions provided the corresponding dienes. These substituted dienes were cyclized by ring closing metathesis at room temperature or under microwave-activation with Grubbs-type II catalyst to yield SES-protected pyrroline intermediates. The final pyrroles were obtained by base-promoted dehydrodesulfinylation/aromatization. The scope of each of these reactions was explored. [ABSTRACT FROM AUTHOR]