XANOMELINE COMPARED TO OTHER MUSCARINIC AGENTS ON STIMULATION OF PHOSPHOINOSITIDE HYDROLYSIS IN-VIVO AND OTHER CHOLINOMIMETIC EFFECTS

Activation of muscarinic mi receptors which are coupled to the phospho inositide (PI) second messenger transduction system is the initial obj ective of cholinergic replacement therapy in Alzheimer's disease. Thus , we evaluated the ability of the selective muscarinic receptor agonis t (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydroly sis 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 admi nistration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating media tion by muscarinic receptors. The non-selective muscarinic agonists pi locarpine, 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 milameli ne, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-ind uced PI stimulation, suggesting that they act as antagonists at PI-cou pled receptors in vivo. The cholinesterase inhibitors, tacrine and phy sostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vive PI hydrolysis. Xanomeline, hexylthio-TZTP an d thiopilocarpine were relatively free of cholinergic side effects, wh ereas milameline, WAL 2014 and SKB 202026 produced non-selective effec ts. Therefore, these data demonstrate that xanomeline selectively acti vates in vive PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomeline's beneficia l clinical effects on cognition in Alzheimers patients. (C) 1998 Elsev ier Science B.V. All rights reserved.