Differentiation of the active site of minaprine from that of phencyclidine in rat hippocampus.
The active site of minaprine (3-(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine) was studied by means of receptor binding and its effect on acetylcholine (ACh) release in rat hippocampus. [3H]Minaprine binding to the hippocampal membrane was inhibited by minaprine, 4-aminopyridine (4-AP) and phencyclidine (PCP) dose-dependently, whereas it was not inhibited by L-glutamate (L-Glu), N-methyl-D-aspartate (NMDA), 2-amino-5-phosphonovalerate (APV), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) or ketamine. [3H]PCP binding was inhibited by PCP and APV in an extensively washed hippocampal membrane. Minaprine, however, failed to inhibit the [3H]PCP binding. [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) binding was inhibited by L-Glu but not by minaprine. NMDA-evoked [3H]ACh release from the rat hippocampal slices was effectively inhibited by PCP. However, minaprine had no effect on the NMDA-evoked [3H]ACh release. Similar results were obtained from the study of [3H]ACh release in the striatum. These results suggest that minaprine exerts its action via the voltage-dependent K+ channel but not via the NMDA receptor-channel complex or sigma receptor.
Chaki
S
S
Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Usuki-Ito
C
C
Muramatsu
M
M
Otomo
S
S
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology*; D010879:Piperazines / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D010879:Piperazines; D010880:Piperidines; D015221:Potassium Channels; D011724:Pyridazines; D016194:Receptors, N-Methyl-D-Aspartate; C006149:minaprine; D016202:N-Methylaspartate; D007649:Ketamine; D015763:2-Amino-5-phosphonovalerate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C026539:preclamol; D010622:Phencyclidine; D000109:Acetylcholine