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

Abstract

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.

A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding

“…The enhanced recognition memory during the test phase indicates that compound 7 reversed the time-delay induced memory deficit. These results support the procognitive property of the 5-HT 6 R antagonist newly identified herein, similarly to the behavior observed in NORT for other 5-HT 6 R antagonists such as SB-74245716, clinically tested for the treatment of Alzheimer’s disease5. The compound was also assessed for binding affinity toward a set of receptors interacting with cognitive enhancer drugs —serotonin 5-HT 1A , 5-HT 2A , 5-HT 4e , and 5-HT 7 , histamine H 3 , muscarinic acetylcholine M 1 , cannabinoid CB 2 , α 2 adrenergic, α 7 nicotinic, and NMDA receptors—1718.…”

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

“…Among 17 antagonists that have reached clinical trials, only one non-sulfonyl and non-indole structure (1, Figure 1) can be found [4,7,10]. The situation has not been improved during last four years, providing new active compounds among 1H-pyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3 -oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14] (Figure 1), thus indicating a strong need to extend the chemical space of 5-HT 6 R ligands. Molecules 2019, 24, x; doi: www.mdpi.com/journal/molecules Serotonin receptors 5-HT6 (5-HT6Rs) seem to be the most intriguing among the members of 5-HTRs family and also highly promising as a target for innovative therapy of CNS (central nervous system)-diseases.…”

“…Among 17 antagonists that have reached clinical trials, only one non-sulfonyl and non-indole structure (1, Figure 1) can be found [4,7,10]. The situation has not been improved during last four years, providing new active compounds among 1Hpyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3′oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14] (Figure 1), thus indicating a strong need to extend the chemical space of 5-HT6R ligands. Predominant sulfone-and indole-containing structures of serotonin receptors 5-HT6 (5-HT6R) ligands found previously: the only one non-sulfonyl and non-indole structure in clinical trials (1) [4]; the most active 5-HT6R agents that represent the chemical families recently found in primary screenings, i.e., 1H-pyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3′-oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14]; the most advanced compounds in clinical trials towards Alzheimer's disease (AD), i.e., Idalopirdine (6), Intepirdine (7) and [15].…”

“…The situation has not been improved during last four years, providing new active compounds among 1Hpyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3′oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14] (Figure 1), thus indicating a strong need to extend the chemical space of 5-HT6R ligands. Predominant sulfone-and indole-containing structures of serotonin receptors 5-HT6 (5-HT6R) ligands found previously: the only one non-sulfonyl and non-indole structure in clinical trials (1) [4]; the most active 5-HT6R agents that represent the chemical families recently found in primary screenings, i.e., 1H-pyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3′-oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14]; the most advanced compounds in clinical trials towards Alzheimer's disease (AD), i.e., Idalopirdine (6), Intepirdine (7) and [15]. (5-HT 6 R) ligands found previously: the only one non-sulfonyl and non-indole structure in clinical trials (1) [4]; the most active 5-HT 6 R agents that represent the chemical families recently found in primary screenings, i.e., 1H-pyrrolo [3,2-c]quinolones (2) [11], N1-azinylsulfonyl-1H-indoles (3) [12], spiro[pyrrolidine-3,3 -oxindoles] (4) [13] and tricyclic pyrano [2,3,4-cd]indoles (5) [14]; the most advanced compounds in clinical trials towards Alzheimer's disease (AD), i.e., Idalopirdine (6), Intepirdine (7) and [15].…”

Synthesis of Quinolino[3′,4′:4,5]pyrrolo[1,2‐f]phenanthridines by Regioselective Sonogashira Reaction Followed by Domino C–N Coupling/Hydroamination/C–H Arylation

“…In order to discover further candidates for applications in medicinal and materials science, synthetic chemists have developed methods for the construction of quinoline‐fused heterocycles. Recent developments have given access to systems with quinoline fused to different heterocycles . Many of these synthesized compounds are possible candidates for medicinal applications, for instance as anti‐inflammatory agents or 5‐HT6 receptor antagonists (Figure ).…”