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.
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. Although 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.
Suzuki
T
T
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan.
Hirooka
K
K
Kanda
K
K
Uesaka
H
H
Hirooka
H
H
Furusawa
K
K
D000109:Acetylcholine / Q000378:metabolism; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D018697:Nootropic Agents / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism
D000814:Aniline Compounds; D001643:Bridged Bicyclo Compounds; D018721:Muscarinic Agonists; C107666:N-(2-(1-azabicyclo(3.3.0)octan-5-yl)ethyl)-2-nitroaniline; D018697:Nootropic Agents; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D002794:Choline; D000109:Acetylcholine