talsaclidine-fumarate and sabcomeline

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimer's disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.

Topics: Adrenergic beta-Antagonists; Adult; Alzheimer Disease; Animals; Bronchial Spasm; Dose-Response Relationship, Drug; Electroencephalography; Female; Guinea Pigs; Heart; Humans; Imines; In Vitro Techniques; Male; Middle Aged; Muscarinic Agonists; Muscle, Smooth; Neurons; Propanolamines; Quinuclidines; Rabbits; Rats; Receptors, Muscarinic

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