PKN phosphorylates tau protein and accumulates in Alzheimer neurofibrillary tangles

S361

830 TSUGIO

CENTRAL KANEKO

ACTIVATION

‘, TOSHIYUKI

BY CS-932, A FUNCTIONALLY

TONOHIRO

I, TAKAO

RELATIVE

HARA ‘, JUNICHI

‘Neurosci.

Res. Labs, *New Lead Res. Labs, Sankyo Co., Ltd., Shinagawa-ku,

Activation

of brain functions

concentration-dependently 932 was antagonized

by a functionally

increased

relative

was intraducdenally

administered.

pirenzepine,

with pentobarbital,

subcutaneously,

dose-dependently

increase in alpha and beta waves. and counteract cholinergic

by carbachol

pathway.

activated

CS-932,

were examined

function

scopolamine-induced

the theta wave power in the rat slow wave EEG in rats. Under

mainly of slow waves.

which waas indicated

by a decrease

agonists

SUGIMOTO

PROFILES

‘, MASAO

of cholinergic esterase

OF CS-932,

KOZUKA

A FUNCTIONALLY

‘, YUSUKE

NAGANO ’ and NOBUYOSHI

activation

inhibitors.

for a treatment

A more specific

for the type-1 of muscarinic

(M,) receptor.

binding to the rat cerebral cortex membranes that on 3H-QNB binding.

in delta waves and an

KONDO’,

SELECTIVE

TOMOKO

activation

M,

IIZAWA’,

AGONIST.

YOICHI

NIITSU

Tokyo 140-87 10

disease has been proved by clinical applications

of central cholinergic

CS-932, a newly synthesized

systems

compound,

can be achieved inhibited

by selective

3H-oxotremorine-M

with an IC50 value of 0.52 pM. This effect was IOO-fold more potent than binding

to cortical

membranes

9.2-fold

more strongly

These results in binding studies indicate that CS-932 is an agonist relatively

CS-932 concentration-dependently by atropine.

increased

free Ca?+ level in CHO cells expressing

This effect was antagonized

formation,

and this effect was weaker than that on free Ca’+ level in M, -CHO cells. In mice, CS-932 showed a high pen-

etration into the brain after an oral administration

832

Ml AGONIST

selective

In Mz-CHO

intracellular

than

selec-

receptors.

that CS-932 is a functionally

‘,

IWATA ’

of Alzheimer’s

CS-932 also inhibited ‘H-pirenzepine

“H-QNB binding to heart membranes. tive to M, receptors.

CS-932, injected

These findings suggest that CS-932 can activate CSN neurons via an Ml receptor stimulation

’Neurosci. Res. Labs, ‘Med. Info. Dept. I, ‘New Lead Res. Labs, Sankyo Co., Ltd., Shinagawa-ku, An effectiveness

The effect of CS-

Cortical cholinoceptive

were activated when the compound

EEG and increased

monkey consisted

CS-933

deficits in the CNS.

SAKAI j, MITSUO

of acetylcholine

z and

models.

slices.

AF-DX116.

applied iontophoretically,

The compound antagonized

the cerebral

in several

neurons in the rat hippocampal

the hippocampal

cortical EEG of cynomologus

PHARMACOLOGICAL

MASAHIKO JUNICHI

NAGANO

Tokyo 140-8710

but not by the M2 antagonist,

CS-932 re-sychronized

in the septohippocampal

light anesthesia

Ml agonist,

firing rate of the cholinoceptive

by the Ml antagonist,

neurons of rats, whose firing rates were increased

831

SAKAI 2, MITSUO

IWATA 1

NOBUYOSHI

denervated

h41 AGONIST.

cells, CS-932 decreased

and low incidence

of salivation

forskolin-stimulated

and hypothermia.

M,

CAMP

These data indicate

agonist of M, receptors.

CS-932 AMELIORATES

LEARNING

DEFICITS

IN EXPERIMENTAL

YUSUKE KONDO ‘, TAKEFUMI KIKUSUI ‘, MASAO KOZUKA’, TSUNEYUKI YAMAMOTO JUNICHI SAKA13, MITSUO NAGANO) AND NOBUYOSHI IWATA’ ‘Neurosci. Res. LabqzMed. Info. Dept. I, ‘New Lead Res. Labs, Sankyo Co., Ltd., Tokyo, 4Dept. Pharrnacol., Faculty Pharmac. Sci., Kyushu Univ., Fukuoka

MODELS.

“,

Central cholinergic deficits, at least at early phase of, Alzheimer disease and an effectiveness of’cholinergic activation for a treatment of the disease have been proved by clinical applications of acetylcholine esterase inhibitors. A more central specific activation of cholinergic systems can be achieved by selective agonists for a central dominant receptor subtype, the type-l of muscarinic (Ml) receptor. A functionally selective Ml agonist, CS-932, prolonged the shortened escape latencies of a passive avoidance tasks in rats with bilateral lesions of the basal forebrain at a dose of 0.3 mg/kg, p.o. A muscarinic antagonist, scopolami~re, markedly increased the goal time and the number of working memory errors in 3-panel runway working task of rats. CS-932 shortened the goal time prolonged by scopolamine at doses of 0.032 mg/kg, p.o. or more. CS-932 reduced the scopolamine-induced errors at doses of 0 1 and 0.32 mg/kg. The two-choice place discrimination task in a water maze has been demonstrated to be sensitive to central muscarinic manipulation as well as to aging. Learning deficits, a reduction of the accuracy, ofthe two-choice discrimination task in aged (22-24 month old) rats were ameliorated by CS-932 at a small dose of 0.3 mg/kg, p.o. without peripheral cholinergic signs. These data suggest that the central Ml activation can be useful for