milameline and xanomeline

Activation of muscarinic m1 receptors which are coupled to the phosphoinositide (PI) second messenger transduction system is the initial objective of cholinergic replacement therapy in Alzheimer's disease. Thus, we evaluated the ability of the selective muscarinic receptor agonist (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydrolysis and compared it to a number of direct acting muscarinic agonists, two cholinesterase inhibitors and a putative m1 agonist/muscarinic m2 antagonist. Using a radiometric technique, it was determined that administration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating mediation by muscarinic receptors. The non-selective muscarinic agonists pilocarpine, oxotremorine, RS-86, S-aceclidine, but not the less active isomer R-aceclidine, also effectively stimulated PI hydrolysis in mice. Amongst the putative m1 agonists, thiopilocarpine, hexylthio-TZTP as well as xanomeline effectively stimulated PI hydrolysis, but milameline, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-induced PI stimulation, suggesting that they act as antagonists at PI-coupled receptors in vivo. The cholinesterase inhibitors, tacrine and physostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vivo PI hydrolysis. Xanomeline, hexylthio-TZTP and thiopilocarpine were relatively free of cholinergic side effects, whereas milameline, WAL 2014 and SKB 202026 produced non-selective effects. Therefore, these data demonstrate that xanomeline selectively activates in vivo PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomeline's beneficial clinical effects on cognition in Alzheimers patients.

Topics: Animals; Binding, Competitive; Brain Chemistry; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Agents; Cholinesterase Inhibitors; Dihydropyridines; Dose-Response Relationship, Drug; Hydrolysis; Hypothermia; Imines; Lithium; Male; Mice; Mice, Inbred Strains; Muscarinic Agonists; Oximes; Parasympathomimetics; Phosphatidylinositols; Physostigmine; Pilocarpine; Pyridines; Quinuclidines; Radioligand Assay; Salivation; Tacrine; Tetrazoles; Thiadiazoles; Tremor

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

This paper reviews the scientific and ethical issues surrounding the conduct of bridging studies in patients with Alzheimer's disease (AD). Bridging studies, so called because they facilitate the transition from phase I to phase II development, are late phase I safety/tolerance studies which determine the maximum tolerated dose (MTD) in patients before initiating phase II efficacy studies. Determining the MTD in patients is important because we have found that AD patients appear to respond to cholinergic compounds differently from normal volunteers, reaching a different MTD. Preliminary evidence of dose-related efficacy with two cholinergic compounds lends support to our contention that determination of the highest tolerated dose maximizes the potential to detect efficacy. We will review the early clinical development of several cholinergic compounds and make recommendations for the design and conduct of bridging studies based on our experience. A fixed-dose panel design with dosages based on the MTD determined in normal volunteers is recommended. In order to minimize risk to the patients, ensuring that scientific benefits outweigh the risks, a bridging study must be supported by detailed preclinical toxicology, by a clinical research unit that is prepared to handle unexpected contingencies, and by the oversight of a competent, multi-disciplinary review board. Patients should be in good physical health (excluding AD), and a comprehensive informed consent procedure must be instituted. Carefully planned and well run bridging studies represent a scientifically and ethically sound approach to drug development in the Alzheimer's population.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Dihydropyridines; Ethics, Medical; Humans; Nootropic Agents; Oximes; Physostigmine; Psychotropic Drugs; Pyridines; Tacrine; Thiadiazoles