Xanomeline compared to other muscarinic agents on stimulation of phosphoinositide hydrolysis in vivo and other cholinomimetic effects.
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.
Bymaster
F P
FP
Lilly Neuroscience Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. f.bymaster@lilly.com
Carter
P A
PA
Peters
S C
SC
Zhang
W
W
Ward
J S
JS
Mitch
C H
CH
Calligaro
D O
DO
Whitesitt
C A
CA
DeLapp
N
N
Shannon
H E
HE
Rimvall
K
K
Jeppesen
L
L
Sheardown
M J
MJ
Fink-Jensen
A
A
Sauerberg
P
P
D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018678:Cholinergic Agents / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006868:Hydrolysis; D007035:Hypothermia / Q000139:chemically induced; D007097:Imines / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010830:Physostigmine / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology; D011869:Radioligand Assay; D012472:Salivation / Q000187:drug effects; D013619:Tacrine / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology*; D014202:Tremor / Q000139:chemically induced
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D004095:Dihydropyridines; D007097:Imines; C108369:LU 25-109-T; D018721:Muscarinic Agonists; D010091:Oximes; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011725:Pyridines; D011812:Quinuclidines; D013777:Tetrazoles; D013830:Thiadiazoles; D010862:Pilocarpine; C084650:aceclidine; C075258:3-(3-(hexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; C096405:PD 142505-0028; D013619:Tacrine; C079885:talsaclidine fumarate; D008094:Lithium; C075257:xanomeline; D010830:Physostigmine; C109640:sabcomeline; C084978:milameline