WAL-2014-FU (TALSACLIDINE) - A PREFERENTIALLY NEURON ACTIVATING MUSCARINIC AGONIST FOR THE TREATMENT OF ALZHEIMERS-DISEASE

The functional selectivity of WAL 2014 FU with regard to stimulation o f the neuronal muscarinic M-1 receptor subtype in vitro and in vivo is shown in different receptor preparations, isolated organ models, whol e animal testing, and finally humans. From receptor binding experiment s in membrane preparations from rat tissues and from Chinese hamster o vary cells expressing human muscarinic receptor subtypes, it can be de lineated that the ratio between M-1 and M-2 (hm1 and hm2) is shifted i n favour of the M-1 receptor affinity when compared to several classic muscarinic agonists such as carbachol, arecoline, and oxotremorine. T he intermediate GTP-shift of 7.5 for WAL 2014 FU in a M-2 muscarinic r eceptor preparation (rat heart) indicates only partial agonistic activ ity at this subtype, carbachol (e.g, shows a shift of 51). Moreover, t he ratio from agonist to antagonist receptor binding comparing the aff inities using [H-3]cis-methyldioxolane and [H-3]N-methylscopolamine as radioligands, suggests only a partial agonist behaviour at M-2 recept ors, too. In functional assays in vitro, such as phosphoinositide brea kdown measured in cerebral cortex slices from guinea pig brain, WAL 20 14 FU is as effective (27.8% compared to carbachol 100%) as arecoline (27.6%), but is more effective than RS 86 (22.1%), oxotremorine (21.6% ) or McN-A-343 (14.7%). WAL 2014 FU is about as effective as RS 86 and McN-A-343 in stimulating the secretion of N-acetyl-glucosaminidase fr om RBL cells transfected with the human m1 receptor subtype. Investiga ting the proton efflux from CHO cells expressing hm1, hm2, and hm3 mus carinic receptor with cytosensor technology WAL 2014 FU was clearly mo re effective at human m1 receptors (66.3% compared to carbachol 100%) than at hm3 receptors (18.6%) and showed no measurable effect at hm2 r eceptor expressing cells. The efficacy in isolated organ preparations and in whole animals has already been reported [Ensinger et al., 1993] and shows the functional selectivity of WAL 2014 FU quite impressivel y. The general receptor profile of WAL 2014 FU demonstrates a nearly s pecific interaction with muscarinic receptors, having only weak bindin g affinity for a(1)- and nicotinic receptors. Results from pharmacokin etic studies in rats and humans indicate high oral bioavailability (>9 5% in rats) and very low interindividual variation in plasma levels. F urthermore, good penetration of the blood brain barrier with 2.5- to 3 -fold higher concentrations of WAL 2014 FU in brain than in plasma cou ld be measured. The advantageous and stable pharmacokinetic profile of WAL 2014 FU and its functional M-1 selectivity establish WAL 2014 FU as a promising candidate for drug treatment of Alzheimer's disease. In addition to its role for symptomatic treatment, WAL 2014 FU may also have a disease-modifying potential because of its stimulatory effects on APP(s) secretion. (C) 1997 Wiley-Liss, Inc.