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Dual 5-HT 6 and D 3 Receptor Antagonists in a Group Of Dual 5-HT 6 and D 3 Receptor Antagonists in a Group of 1 H -Pyrrolo[3,2- c ]quinolines with Neuroprotective and Procognitive Activity Katarzyna Grychowska, Séverine Chaumont-Dubel, Rafal Kurczab, Paulina Koczurkiewicz, Caroline Deville, Martyna Krawczyk, Wojciech Pietruś, Grzegorz Satala, Kamil Piska, Marcin Drop, et al. To cite this version: Katarzyna Grychowska, Séverine Chaumont-Dubel, Rafal Kurczab, Paulina Koczurkiewicz, Caroline Deville, et al.. Dual 5-HT 6 and D 3 Receptor Antagonists in a Group of 1 H -Pyrrolo[3,2- c ]quinolines with Neuroprotective and Procognitive Activity. ACS Chemical Neuroscience, American Chemical Society (ACS), 2019, 10 (7), pp.3183-3196. 10.1021/acschemneuro.8b00618. hal-02364291 HAL Id: hal-02364291 https://hal.umontpellier.fr/hal-02364291 Submitted on 29 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Page 1 of 36 ACS Chemical Neuroscience 1 2 3 Dual 5-HT and D Receptors Antagonists in a Group of 1H-Pyrrolo[3,2- 4 6 3 5 c]quinolines with Neuroprotective and Pro-cognitive Activity 6 7 8 9 10 11 Katarzyna Grychowska,a Severine Chaumont-Dubel,b Rafał Kurczab,c Paulina 12 d a e c c 13 Koczurkiewicz, Caroline Deville, Martyna Krawczyk, Wojciech Pietruś, Grzegorz Satała, 14 Kamil Piska,d Marcin Drop,a Xavier Bantreil,f Frédéric Lamaty,f Elżbieta Pękala,d 15 16 Andrzej J. Bojarski,c Piotr Popik,e Philippe Marin,b Paweł Zajdela,* 17 18 19 20 21 22 23 a d 24 Department of Medicinal Chemistry, and Department of Pharmaceutical Biochemistry 25 Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland 26 27 c Department of Medicinal Chemistry, eDepartment of Behavioral Neuroscience and Drug 28 29 Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 30 31 31-343 Kraków, Poland 32 b IGF, Université de Montpellier, CNRS INSERM, Montpellier, France 33 34 f IBMM, UMR 5247, CNRS, Université de Montpellier, ENSCM, Place Eugène Bataillon, 35 36 34095 Montpellier, France 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 *Corresponding author: 53 Paweł Zajdel 54 Department of Medicinal Chemistry 55 56 Jagiellonian University Medical College 57 E-mail: [email protected] 58 Tel.: +48 126205450 59 60 1 ACS Paragon Plus Environment ACS Chemical Neuroscience Page 2 of 36 1 2 3 Abstract 4 5 6 7 In light of the multifactorial origin of neurodegenerative disorders and some body of 8 9 evidence indicating that pharmacological blockade of serotonin 5-HT6 and dopamine D3 10 11 receptors might be beneficial for cognitive decline, we envisioned (S)-1-[(3- 12 chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (CPPQ), a 13 14 neutral antagonist of 5-HT6R, as a chemical template for designing dual antagonists of 5- 15 16 HT6/D3 receptors. As shown by in vitro experiments, supported by quantum chemical 17 calculations and molecular dynamic simulations, introducing alkyl substituents at the 18 19 pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 20 21 5-HT6 and D3 receptors. 22 23 The study identified compound 19 ((S)-1-((3-chlorophenyl)sulfonyl)-N-(1- 24 isobutylpyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine), which was classified as a dual 5- 25 26 HT6/D3Rs antagonist (Ki (5-HT6) = 27 nM, Ki (D3) = 30 nM). Compound 19 behaved as a neutral 27 28 antagonist at Gs signaling and had no influence on receptor-operated, cyclin-dependent kinase 29 30 5 (Cdk-5)-dependent neurite growth. In contrast to the well characterized 5-HT6R antagonist 31 intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage 32 33 induced by doxorubicine, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium 34 35 (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an 36 index of cell membrane disruption. This feature is of particular importance considering the 37 38 involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. 39 40 Biological results obtained for 19 in in vitro tests, translated into pro-cognitive properties in 41 42 phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in 43 rats. 44 45 46 47 48 Key words: 49 50 5-HT6R antagonists, D3R antagonists, Cdk5 signaling pathway, multifunctional ligands, salt 51 52 bridge, molecular dynamics, neuroprotection, astrocytes, novel object recognition test 53 54 55 56 57 58 59 60 2 ACS Paragon Plus Environment Page 3 of 36 ACS Chemical Neuroscience 1 2 3 Introduction 4 5 6 Cognitive impairment is a common feature of neurodegenerative and psychiatric diseases. 7 This type of decline involves a variety of cognitive domains, including memory, attention, 8 9 language comprehension and problem-solving skills.1 Deficits in these functions contribute to 10 11 a poor level of social interaction and decreased quality of life. Although various procognitive 12 13 drug candidates have been investigated in clinical trials for cognitive dysfunctions in 14 Alzheimer’s disease (AD) and schizophrenia, no disease modifying treatment has been 15 16 clinically validated so far. Thus, development of new compounds for symptomatic 17 18 pharmacotherapy still seems to be a valid strategy. 19 20 Because of the multifactorial etiology of neurodegenerative and psychiatric disorders, 21 selective drugs have shown limited efficacy in clinical trials.2,3 One example is represented by 22 23 serotonin 5-HT6R antagonists, which have been widely explored as potential therapy for 24 25 memory decline in AD. According to recent clinical reports, the positive effects of idalopirdine 26 and intepirdine on memory deficits have not been confirmed in phase III clinical trials. 27 28 Nevertheless, the exact cause of these results remain unclear and 5-HT6R antagonism is still 29 30 being investigated in both preclinical and clinical studies.4–6 31 32 The constant interest in 5-HT6R ligands results from the unique properties of this protein. 33 The 5-HT R belongs to the G-protein coupled receptors (GPCRs) family and displays high level 34 6 35 of constitutive activity at Gs signaling. It also engages additional signaling pathways, such as 36 37 extracellular kinase 1/2 (ERK1/2)7 and cyclin dependent kinase 5 (Cdk5), the latter being 38 8,9 39 involved in neurogenesis process. 5-HT6R also recruits several proteins of the mechanistic 40 Target Of Rapamycin (mTOR) pathway which accounts for the impact of the receptor in some 41 10,11 42 cognition paradigms in rodents(Figure 1). An additional particular feature of the 5-HT6R is 43 44 its exclusive localization in the central nervous system, especially in brain regions involved in 45 learning and memory processes including the prefrontal cortex, hippocampus and stratium.12,13 46 47 Because 5-HT6R blockade enhances cholinergic, glutamatergic and noradrenergic 48 49 transmission, this mechanism has been involved in the improvement of cognitive performance 50 14–17 51 induced by 5-HT6R antagonists (Figure 1). 52 Another molecular target, which has emerged as promising for developing novel pro- 53 54 cognitive drugs, is dopamine D3R. This GPCR is localized in the limbic areas of the brain. In 55 18 56 addition to coupling to Gi/0 protein, it engages other transduction pathways, including Cdk5 57 19 58 and mTOR pathways. An additional value of this mechanism of action is the possibility of 59 60 3 ACS Paragon Plus Environment ACS Chemical Neuroscience Page 4 of 36 1 2 3 20,21 enhancing the acetylcholine and glutamate signalling. Therefore, blockade of D3R may 4 5 improve cognitive decline and also relieve the negative symptoms of psychosis (Figure 1).22 6 7 8 9 10 11 12 13 14 Figure 1. Schematic representation of the hypothetical influence of dual 5-HT /D Rs 15 6 3 16 antagonists on cognitive functions. 17 18 19 20 Because cognitive decline is a common symptom of CNS diseases characterized by a 21 loss of neuronal cells, neuroprotective properties may be a valuable add-on effect of 22 23 pharmacotherapy. Among glial cells, astrocytes play a crucial role in the viability and 24 25 physiological function of neurons by maintaining proper function of the CNS 26 microenviroment.23 Astrocytes supply neurons with vital metabolites, initiate cell repair 27 28 systems and release cytokines and growth factors that exert multidirectional effects. The 29 30 supporting role of astrocytes in the CNS confers them with intrinsic neuroprotective 31 24 32 properties. 33 The aforementioned observation provided the impetus to design dual 5-HT6/D3Rs 34 35 antagonists that display neuroprotective properties in cellular assays and ameliorate cognitive 36 37 decline in animal models. Hence, we envisioned introducing various alkyl chains at the nitrogen 38 39 atom of pyrrolidine in the CPPQ (a neutral 5-HT6R antagonist with pro-cognitive properties) 40 scaffold (Figure 2).25 This approach involved the idea of merged ligands, in which alkyl chains, 41 42 representing pharmacophore fragment of D3R antagonists, were combined with 5-HT6R 43 44 antagonist template. 45 Selective 5-HT6R antagonist Designed derivatives Selective D3 antagonists 46 47 OH O N N 48 Cl X H 49 O O Cl 50 S O S alkyl 51 O N O N Eticlopride 52 NH N 53 N N N Y O O H N 54 N 55 CPPQ H 56 Ki 5-HT6 = 3 nM Kb 5-HT6 = 0.41 nM CN 57 Nafadotride 58 59 Figure 2.
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