ABSTRACT
Research in Alzheimer's disease is going through a big turnaround. New palliative therapies are being reconsidered for the effective management of disease because of setbacks in the development of disease-modifying therapies. Serotonin 6 (5-HT6) receptor has long been pursued as a potential target for the symptomatic treatment of Alzheimer's disease. SUVN-502 is a novel 5-HT6 receptor antagonist (Ki=2.04 nmol/l) with high receptor affinity and high degree of selectivity. SUVN-502 at doses ranging from 1 to 10 mg/kg, per os (p.o.) demonstrated procognitive effects in various behavioral animal models (object recognition task, water maze, and radial arm maze), and it acts on three phases of cognition, viz., acquisition, consolidation, and retention (object recognition task). SUVN-502 (3 and 10 mg/kg, p.o.) modulated glutamate levels when administered alone (microdialysis). At doses ranging from 1 to 10 mg/kg p.o., SUVN-502 potentiated the effects of donepezil (microdialysis). SUVN-502 [1 mg/kg, intravenous (i.v.)] also potentiated pharmacological effects of memantine (1 mg/kg, i.v.) and/or donepezil (0.3 mg/kg, i.v.) (θ modulation). The beneficial effects of SUVN-502 on learning and memory might be mediated through the modulation of cholinergic and/or glutamatergic neurotransmission in relevant brain regions. In summary, behavioral, neurochemical, and electrophysiological outcomes indicate that SUVN-502 may augment the beneficial effects of donepezil and memantine combination.
Subject(s)
Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Indoles/pharmacology , Piperazines/pharmacology , Serotonin Antagonists/pharmacology , Acetylcholine/pharmacology , Animals , Brain Waves/drug effects , CHO Cells , Cricetulus , Culture Media, Serum-Free/pharmacology , Dizocilpine Maleate/pharmacology , Donepezil/pharmacology , Dose-Response Relationship, Drug , Electroencephalography , Glutamic Acid/pharmacology , Male , Maze Learning/drug effects , Memantine/pharmacology , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Microdialysis , Nootropic Agents/pharmacology , Rats , Rats, Wistar , Receptors, Serotonin/metabolism , Recognition, Psychology/drug effects , Scopolamine/toxicity , Serotonin/metabolismABSTRACT
The design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5-HT(6) receptor antagonist activity is presented. The racemic compound 15e was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition.
Subject(s)
Amines/chemistry , Carbazoles/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemistry , Sulfonamides/chemistry , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Brain/metabolism , Carbazoles/chemical synthesis , Carbazoles/pharmacokinetics , Half-Life , Humans , Male , Microsomes, Liver/metabolism , Rats , Rats, Wistar , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacokinetics , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
A series of N(1)-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N(1)-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT(6) receptor. Several compounds displayed potent binding affinity for the 5-HT(6) receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C(3) of indole carbon maintains the binding affinity to 5-HT(6)R. The lead compound N(1)-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a (K(b)=0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze.