Effect of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b] quinolin-4-yl)acetoamide on deficits of water maze learning in rats.
The pharmacological properties of MKC-231 (2-(2-oxopyrrolidin-1-yl)-N- (2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl) acetoamide, CAS 135463-81-9) in comparison with an acetylcholinesterase (AChE) inhibitor, tacrine (CAS 1684-40-8) were studied. MKC-231(10(-10)-10(-6) moll) significantly increased high affinity choline uptake (HACU) when it was incubated with the hippocampal synaptosomes of ethylcholine mustard aziridinium ion (AF64A) treated rats, but not of normal rats. MKC-231 did not affect the AChE activity, [3H]- quinuclidinyl benzilate binding, and [3H]-pirenzepine binding. Oral administration of MKC-231 (1-10 mg/kg) significantly improved the learning deficits in the Morris' water maze of AF64A-treated rats, but it did not produce any significant side effects, like tremor, salivation or hypothermia, which were observed in rats treated with high doses of tacrine. Tacrine (0.1-3 mg/kg p.o.) failed to ameliorate the learning deficits in AF64A-treated rats. These results suggest that MKC-231 is a novel and quite unique compound, which improves the memory impairment induced by AF64A through the enhancement of HACU without any side effects at the effective doses.
Bessho
T
T
Pharmaceuticals Laboratory 1, Yokohama Research Center, Mitsubishi Chemical Corporation, Japan.
Takashina
K
K
Tabata
R
R
Ohshima
C
C
Chaki
H
H
Yamabe
H
H
Egawa
M
M
Tobe
A
A
Saito
K
K
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D002794:Choline / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D013619:Tacrine / Q000494:pharmacology; D014202:Tremor / Q000139:chemically induced
D001388:Aziridines; D009466:Neuromuscular Blocking Agents; D018697:Nootropic Agents; D011804:Quinolines; D011976:Receptors, Muscarinic; D013619:Tacrine; C044894:ethylcholine aziridinium; D000110:Acetylcholinesterase; D002794:Choline; C092988:MKC 231