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.
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.
Katarzyna
K
Grychowska
Grzegorz
G
Satała
Tomasz
T
Kos
Anna
A
Partyka
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Université de Montpellier Campus Triolet Place Eugène Bataillon, 34095 CEDEX 5 Montpellier, France.
Evelina
E
Colacino
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université de Montpellier, Montpellier 34094, France.
Severine
S
Chaumont-Dubel
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Université de Montpellier Campus Triolet Place Eugène Bataillon, 34095 CEDEX 5 Montpellier, France.
Xavier
X
Bantreil
Anna
A
Wesołowska
Maciej
M
Pawłowski
Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie 15, avenue Charles Flahault BP14491, 34093 CEDEX 5 Montpellier, France.
Jean
J
Martinez
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université de Montpellier, Montpellier 34094, France.
Philippe
P
Marin
Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie 15, avenue Charles Flahault BP14491, 34093 CEDEX 5 Montpellier, France.
Gilles
G
Subra
Andrzej J
AJ
Bojarski
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Université de Montpellier Campus Triolet Place Eugène Bataillon, 34095 CEDEX 5 Montpellier, France.
Frédéric
F
Lamaty
Piotr
P
Popik
Paweł
P
Zajdel
D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications; D000818:Animals; D016466:CHO Cells; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000473:pathology; D010622:Phencyclidine / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D013450:Sulfones / Q000737:chemistry / Q000627:therapeutic use
C581185:1H-pyrrolo(3,2-h)quinoline; C548140:3-benzenesulfonyl-8-piperazin-1-ylquinoline; D011758:Pyrroles; D011804:Quinolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; D000242:Cyclic AMP; D010622:Phencyclidine
5-HT6R antagonist; 5-HT6R inverse agonist; Alzheimer’s disease; SB-742457, cognition; Vogel test; forced swim test; memory; novel object recognition test; pyrrolo[3,2-c]quinoline