sb-271046 and Alzheimer-Disease

Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.

Topics: Alzheimer Disease; Binding Sites; Clinical Trials as Topic; Cognition Disorders; Humans; Models, Molecular; Molecular Structure; Protein Structure, Tertiary; Receptors, Serotonin; Serotonin Antagonists

Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT

Topics: Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Electrophorus; Humans; Locomotion; Male; Mice; Models, Molecular; Molecular Structure; Prodrugs; Receptors, Serotonin; Structure-Activity Relationship

5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Chemistry Techniques, Synthetic; Drug Design; Guinea Pigs; HEK293 Cells; Humans; Ligands; Male; Mice; Molecular Targeted Therapy; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

5-HT(6) receptor subtype is predominantly expressed in the brain, and preclinical evidence suggests its potential role in the cognitive function. Brain microdialysis studies demonstrated that 5-HT(6) antagonists enhance not only cholinergic but also monoaminergic neurotransmission, a property that may differentiate from acetylcholine esterase (AChE) inhibitors such as donepezil. In this study we compared the antidepressant-like effects of 5-HT(6) antagonists with donepezil to determine whether their different effects on monoamines are behaviorally relevant.. Selective 5-HT(6) antagonists (SB-399885 and SB-271046) and donepezil were evaluated in the rat forced swimming test since this is known to identify drugs such as antidepressants which can increase brain monoamine levels. Binding assay was undertaken by using [(125)I]SB-258585 to measure brain 5-HT(6) receptor occupancy.. Systemic administration of SB-399885 (3 and 10 mg/kg, i.p.) and SB-271046 (10 and 30 mg/kg, i.p.) produced a significant reduction of immobility time in the rat forced swimming test with a similar profile in terms of 5-HT(6) receptor occupancy (62 and 96% for 3 and 10 mg/kg SB-399885 respectively; 56 and 84% for 10 and 30 mg/kg SB-271046 respectively). In contrast, donepezil (0.5 and 1 mg/kg i.p.) did not show any effects in this model.. These data suggest that 5-HT(6) antagonists, at doses corresponding to those occupy central 5-HT(6) receptors, could have an antidepressive effect in humans. This may differentiate 5-HT(6) antagonists from AChE inhibitors with respect to the mood control in the symptomatic treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Cognition; Male; Mood Disorders; Piperazines; Protein Binding; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Sulfonamides; Swimming; Thiophenes