CHARACTERIZATION OF THE NEUROCHEMICAL EFFECTS OF 1-AZABICYCLO[3,3,0]OCTAN-5-YL)ETHYL]2-NITROANILINE FUMARATE (SK-946) AS A COGNITION ACTIVATOR

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.