piperidines and xanomeline

The standards of care for Alzheimer's disease, acetylcholinesterase inhibitors such as donepezil (Aricept®), are dose-limited due to adverse side-effects. These adverse events lead to significant patient non-compliance, constraining the dose and magnitude of efficacy that can be achieved. Non-selective muscarinic receptor orthosteric agonists such as Xanomeline have been shown to be effective in treating symptoms as well, but were also poorly tolerated. Therefore, there is an unmet medical need for a symptomatic treatment that improves symptoms and is better tolerated.. We compared donepezil, xanomeline, and the novel selective muscarinic 1 receptor positive allosteric modulator PQCA in combination with donepezil in the object retrieval detour (ORD) cognition test in rhesus macaque. Gastrointestinal (GI) side effects (salivation and feces output) were then assessed with all compounds to determine therapeutic window.. All three compounds significantly reduced a scopolamine-induced deficit in ORD. Consistent with what is observed clinically in patients, both donepezil and xanomeline produced significant GI effects in rhesus at doses equal to or less than a fivefold margin from the minimum effective dose that improves cognition. In stark contrast, PQCA produced no GI side effects when tested at the same dose range.. These data suggest M1 positive allosteric modulators have the potential to improve cognition in Alzheimer's disease with a greater therapeutic margin than the current standard of care, addressing an important unmet medical need.

Topics: Aged; Alzheimer Disease; Animals; Appetitive Behavior; Attention; Cognition; Defecation; Donepezil; Female; Humans; Indans; Macaca mulatta; Male; Muscarinic Agonists; Neuropsychological Tests; Orientation; Piperidines; Problem Solving; Pyridines; Quinolizines; Receptor, Muscarinic M1; Salivation; Thiadiazoles

Novel bitopic hybrids, based on the M1/M4 muscarinic acetylcholine receptor (mAChR) orthosteric agonist xanomeline (1) and the putative M1 mAChR allosteric agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 3) connected by an aliphatic linker of variable length, were prepared. The novel heterobivalent hybrids 4a-f along with the intermediate alcohols 5a-f were pharmacologically evaluated in radioligand binding assays and some of them for their functional efficacies in bioluminescence resonance energy transfer (BRET)-based assays to give an insight into the structure-activity relationships of bivalent and linker-attached compounds in mAChRs. The hybrid 4d exhibited high efficacy for β-arrestin2 engagement in M1 mAChR and alcohol 5c behaved much like 3 at M1 mAChR and showed full antagonism in both Gi activation and β-arrestin2 engagement at M4 mAChR. Moreover, docking simulations on the M1 mAChR model were performed to elucidate how the binding mode of the proposed compounds is influenced by the linker length.

Topics: Animals; CHO Cells; Cricetulus; Molecular Docking Simulation; Muscarinic Agonists; Piperidines; Pyridines; Quinolones; Receptor, Muscarinic M1; Structure-Activity Relationship; Thiadiazoles

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Dihydropyridines; Donepezil; Humans; Indans; Muscarinic Agonists; Oximes; Phenylcarbamates; Piperidines; Pyridines; Rivastigmine; Tacrine; Thiadiazoles