Neurochemical effects of the M1 muscarinic agonist xanomeline (LY246708/NNC11-0232).
Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-me thylpyridine)] was evaluated in vivo in rat brain for effects on neurotransmitter turnover and inhibition of ex vivo binding of muscarinic radioligands. Xanomeline produced dose-related increases in the metabolite of dopamine, dihydroxyphenylacetic acid (DOPAC), in striatum. The increases in striatal DOPAC levels produced by xanomeline were antagonized by the relatively selective M1 antagonist trihexyphenidyl, suggesting that xanomeline interacts with M1 heteroreceptors on dopamine nerve terminals. Xanomeline produced small increases in striatal acetylcholine levels and did not antagonize the large increases in acetylcholine produced by the nonselective muscarinic agonist oxotremorine, indicating that xanomeline did not block M2 autoreceptors. Xanomeline inhibited ex vivo binding of muscarinic radioligands to homogenates of brain and the inhibition of ex vivo binding occurred in the same dose range as increases in DOPAC levels. Xanomeline did not appreciably induce salivation or antagonize oxotremorine-induced salivation indicating that xanomeline does not interact with M3 receptors. The effects of xanomeline on ex vivo binding and DOPAC levels lasted for about 3 hr and were evident after oral administration. An analog of xanomeline with similar in vivo effects did not inhibit acetylcholinesterase or choline acetyltransferase and inhibited choline uptake only at concentrations much higher than those required to inhibit binding. These data indicate xanomeline is selective agonist for M1 over M2 and M3 receptors in vivo in rat. It is not known whether xanomeline interacts with m4 or m5 receptors in vivo.
Bymaster
F P
FP
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis.
Wong
D T
DT
Mitch
C H
CH
Ward
J S
JS
Calligaro
D O
DO
Schoepp
D D
DD
Shannon
H E
HE
Sheardown
M J
MJ
Olesen
P H
PH
Suzdak
P D
PD
Swedberg
M D
MD
Sauerberg
P
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002794:Choline / Q000493:pharmacokinetics; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010277:Parasympathomimetics / Q000378:metabolism / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012472:Salivation / Q000187:drug effects; D013830:Thiadiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D018377:Neurotransmitter Agents; D014179:Neurotransmitter Uptake Inhibitors; D010277:Parasympathomimetics; D011619:Psychotropic Drugs; D011725:Pyridines; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D015102:3,4-Dihydroxyphenylacetic Acid; C075257:xanomeline; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002794:Choline; D000109:Acetylcholine