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Novel 1H-Pyrrolo[3,2-C]Quinoline Based 5-HT6 Receptor Antagonists

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Novel 1H-Pyrrolo[3,2-C]Quinoline Based 5-HT6 Receptor Antagonists Novel 1H-Pyrrolo[3,2-c]quinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer’s Disease Katarzyna Grychowska, Grzegorz Satala, Tomasz Kos, Anna Partyka, Evelina Colacino, Severine Chaumont-Dubel, Xavier Bantreil, Anna Wesolowska, Maciej Pawlowski, Jean Martinez, et al. To cite this version: Katarzyna Grychowska, Grzegorz Satala, Tomasz Kos, Anna Partyka, Evelina Colacino, et al.. Novel 1H-Pyrrolo[3,2-c]quinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer’s Disease. ACS Chemical Neuroscience, American Chemical Society (ACS), 2016, 7 (7), pp.972–83. 10.1021/acschemneuro.6b00090. hal- 01941175 HAL Id: hal-01941175 https://hal.archives-ouvertes.fr/hal-01941175 Submitted on 5 Feb 2021 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. Research Article pubs.acs.org/chemneuro H‑ ‑c ‑ Novel 1 Pyrrolo[3,2 ]quinoline Based 5 HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer’s Disease † § ∥ ‡ ⊥ Katarzyna Grychowska, Grzegorz Satała, Tomasz Kos, Anna Partyka, Evelina Colacino, # ⊥ ‡ † ∇ Severine Chaumont-Dubel, Xavier Bantreil, Anna Wesołowska, Maciej Pawłowski, Jean Martinez, # ∇ § ⊥ ∥ † Philippe Marin, Gilles Subra, Andrzej J. Bojarski, Fredérić Lamaty, Piotr Popik, and Paweł Zajdel*, † ‡ Department of Medicinal Chemistry, and Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland § ∥ Department of Medicinal Chemistry, and Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland ⊥ Institut des Biomoleculeś Max Mousseron (IBMM), UMR 5247, CNRS, Universitéde Montpellier, ENSCM, Universitéde Montpellier Campus Triolet Place Eugenè Bataillon, 34095 CEDEX 5 Montpellier, France # Institut de Genomiqué Fonctionnelle, CNRS UMR 5203, INSERM U661, Universitéde Montpellier, Montpellier 34094, France ∇ Institut des Biomoleculeś Max Mousseron (IBMM) UMR 5247, CNRS, Universitéde Montpellier, ENSCM, Facultéde Pharmacie 15, avenue Charles Flahault BP14491, 34093 CEDEX 5 Montpellier, France *S Supporting Information ff ABSTRACT: Modulators of the serotonin 5-HT6 receptor (5-HT6R) o er 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 fi the identi cation 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. KEYWORDS: 5-HT6R antagonist, 5-HT6R inverse agonist, pyrrolo[3,2-c]quinoline, SB-742457, cognition, memory, novel object recognition test, forced swim test, Vogel test, Alzheimer’s disease lzheimer’s disease (AD), an irreversible neurodegenerative symptomatic treatment without affecting the neurodegenera- A disorder, is the most common form of dementia world- tion process.1 wide. AD is characterized by the progressive deterioration of In recent years, the serotonin 5-HT6 receptor (5-HT6R) has various cognitive domains, including a decline in memory emerged as a promising molecular target for the treatment of and thinking. More than 35 million people are suffering from AD. Currently available therapeutic options for the treat- Received: March 23, 2016 ment of AD, based on acetylcholinesterase inhibitors and Accepted: April 21, 2016 NMDA receptor antagonist, provide modest efficacy and Published: April 21, 2016 © 2016 American Chemical Society 972 DOI: 10.1021/acschemneuro.6b00090 ACS Chem. Neurosci. 2016, 7, 972−983 ACS Chemical Neuroscience Research Article fi 2 cognitive de cits in AD. The 5-HT6R belongs to the family of G-protein coupled receptors, which are positively coupled with adenylyl cyclase. Additionally, 5-HT6Rs engage extracellular signal-regulated kinase (ERK)1/2 pathway via the Src family tyrosine kinase Fyn,3 as well as cyclin-dependent kinase (Cdk)5,4 and mammalian Target Of Rapamycin (mTOR) pathways.5 Moreover, nonphysiological mTOR activation in prefrontal fi cortex, under the control of 5-HT6R, underlies de cits in social cognition and episodic memory in two neurodevelopmental models of schizophrenia in the rat, neonatal administration of the NMDA receptor antagonist phencyclidine and rearing in social Figure 2. Structures of 5-HT6R antagonists evaluated in phase 3 clinical 5 trials. isolation after the weaning. 5-HT6R displays high constitutive activity at various signaling cascades, including Gs adenylyl 6 4 produced procognitive and/or antiamnesic effects in other cyclase, and Cdk5 pathways. Accordingly, the deleterious ’ fl fl neuropsychiatric disorders, i.e. schizophrenia, and Parkinson s in uence of 5-HT6R in AD may re ect an alteration in receptor disease, and might open therapeutic opportunity for autism expression as well as a deregulation of its activity. The 5-HT6R treatment.5,18 is almost exclusively expressed in the CNS, with high levels in ff Continuing our e orts to generate selective 5-HT6R ligands, the prefrontal cortex, hippocampus, and striatum, the brain we applied a scaffold-hopping approach to fuse a pyrrole ring regions that are predominantly involved in the learning and 7 onto the c edge of the quinoline fragment of 6-nitroquipazine memory processes. It has also been demonstrated that 5-HT6R (selective serotonin-reuptake inhibitor) and then replaced the antagonists modify the transmission of acetylcholine, glutamate, 8,9 piperazine moiety with its 3-aminopyrrolidine bioisostere. dopamine, and norepinephrine. Although the resulting N-4-(pyrrolidin-3-yl-amino)-1H-pyrrolo- The progress in development of 5-HT6R modulators has [3,2-c]quinoline I, displayed a low affinity for the 5-HT R, recently been comprehensively reviewed by Holenz et al.,10 6 11 12 further functionalization of I, introducing the phenylsulfonyl Glennon et al., and Benhamu et al. Important research in the moiety on the nitrogen atom of pyrrole (II), fulfilled the field led to the discovery of several classes of indole and indole- fi structural requirements of a 5-HT6R antagonist and signi cantly like derivatives (e.g., benzofurans, indazoles, pyrazolopyrimidines, ’ ffi increased the compound sa nity for the 5-HT6R. This result indolines) that preferentially bind to the 5-HT6R and behave as prompted us to further investigate the substitution pattern of the antagonists at these sites (Figure 1).13 arylsulfonyl fragment of derivative II to develop potent 5-HT6R antagonists (Figure 3). Figure 3. Strategy to develop a new group of 5-HT6R antagonists. Herein, we report on a small series of arylsulfonyl derivatives of a novel molecular framework that is based on N-4-(pyrrolidin-3- yl-amino)-1H-pyrrolo[3,2-c]quinoline as potent and selective 5-HT6R antagonists. The most promising derivatives were evaluated for their ability to reverse drug-induced memory deficits and for their procognitive properties in novel object Figure 1. Representatives of 5-HT6R antagonists from various recognition test in rats. Because noncognitive traits are often chemotypes. associated with dementia and Alzheimer’s disease, the most promising derivatives were also evaluated in animal models of As a consequence, the structural requirements for 5-HT6R anxiety and depression. antagonists have been described, and pharmacophore models for 14 ■ CHEMISTRY 5-HT6R antagonists have been developed. It is worth noting that 5-HT6R antagonists displayed The designed compounds were synthesized according to a multi- procognitive effects in several learning and memory in vivo step procedure (Scheme
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