Characterization of the Neurochemical Effects of N-[2-(1-azabicyclo[3, 3, 0]octan-5-yl)ethyl]2-nitroaniline fumarate (SK-946) as a Cognition Activator

• Published in: Biological & pharmaceutical bulletin 1998/07/15, Vol.21(7), pp.704-709
• Main Authors: SUZUKI, Tsunemasa, HIROOKA, Kiyotaka, KANDA, Kazumi, UESAKA, Hiroshi, HIROOKA, Hiroko, FURUSAWA, Kenichi
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Binding, Competitive; Biological and medical sciences; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacology; Cells, Cultured; central nervous system; Choline - metabolism; cognition activator; Hippocampus - drug effects; Hippocampus - metabolism; Humans; In Vitro Techniques; Male; Medical sciences; Microdialysis; Muscarinic Agonists - chemistry; Muscarinic Agonists - pharmacology; muscarinic receptor; Neuropharmacology; Neuroprotective agent; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Inbred F344; Rats, Wistar; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - genetics; Recombinant Proteins - metabolism; SK-946
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.21.704

The neurochemical effects of SK-946, N-[2-(1-azabicyclo[3, 3, 0]octan-5-yl)ethyl]2-nitroaniline fumarate, were investigated in an attempt to elucidate cognition activating properties. In rat brain cortical membranes and in cloned human receptors expressed in Sf9 cells, SK-946 had submicromolar affinities for muscarinic receptors with a moderate selectivity for M1 (m1) sites. Althouth no increase in the antagonist (N-methylscopolamine)/agonist (oxotremorine-M) binding ratio was observed, SK-946 exhibited a partial agonistic effect on receptor-stimulated phosphoinositide hydrolysis in primary cultured rat fetal hippocampal cells. Heterogeneous, reversible and concentration-dependent excitations of the hippocampal neuronal cells treated with SK-946 (10-5-10-3 M) were confirmed as increases in cytosolic Ca2+ concentrations measured in Fura-PE3 preloaded cells. Furthermore, SK-946 (>10-5 M) increased [3H]myo-inositol uptake into the hippocampal cells. On the other hand, SK-946 had no effect on adenylate cyclase activities in primary cultured rat heart cells, and showed a weak antagonistic effect on carbachol-induced adenylate cyclase inhibition, suggesting that it is an M2 antagonist. Using in vivo microdialysis, it was found that relatively low concentrations (>10-7 M) of SK-946 increased acetylcholine release and decreased choline content in that hippocampal area in rats. These results suggest that SK-946 accelerates muscarinic neuronal transmission in the central nervous system.