T. Suzuki et al., CHARACTERIZATION OF THE NEUROCHEMICAL EFFECTS OF 1-AZABICYCLO[3,3,0]OCTAN-5-YL)ETHYL]2-NITROANILINE FUMARATE (SK-946) AS A COGNITION ACTIVATOR, Biological & pharmaceutical bulletin, 21(7), 1998, pp. 704-709
The neurochemical effects of SK-946, 1-azabicyclo[3,3,0]octan-5-yl)eth
yl]2-nitroaniline fumarate, were investigated in an attempt to elucida
te cognition activating properties. In I.at brain cortical membranes a
nd in cloned human receptors expressed in Sf9 cells, SK-946 had submic
romolar affinities for muscarinic receptors with a moderate selectivit
y for M-1 (m1) sites. Although no increase in the antagonist (N-methyl
scopolamine)/agonist (oxotremorine-M) binding ratio was observed, SK-9
46 exhibited a partial agonistic effect on receptor-stimulated phospho
inositide hydrolysis in primary cultured rat fetal hippocampal cells.
Heterogeneous, reversible and concentration-dependent excitations of t
he hippocampal neuronal cells treated with SK-946 (10(-5)-10(-3) M) we
re confirmed as increases in cytosolic Ca2+ concentrations measured in
Fura-PE3 preloaded cells. Furthermore, SK-946 (>10(-5) M) increased [
H-3]myo-inositol uptake into the hippocampal cells. On the other hand,
SK-946 had no effect on adenylate cyclase activities in primary cultu
red rat heart cells, and showed a weak antagonistic effect on carbacho
l-induced adenylate cyclase inhibition, suggesting that it is an M-2 a
ntagonist. Using in vivo microdialysis, it was found that relatively l
ow concentrations (<10(-7) M) of SK-946 increased acetylcholine releas
e and decreased choline content in that hippocampal al ea in rats, The
se results suggest that SK-946 accelerates muscarinic neuronal transmi
ssion in the central nervous system.