Ameliorating effect of SA4503, a novel sigma 1 receptor agonist, on memory impairments induced by cholinergic dysfunction in rats.
We found a potent and selective sigma 1 receptor agonist, SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydro-chloride), with high affinity for the sigma 1 receptor subtype (IC50 = 17 nM), but low affinity for the sigma 2 receptor subtype (IC50 = 1800 nM). The binding activity and selectivity of SA4503 resembled those of (+)-pentazocine, a prototype sigma 1 receptor agonist. We have previously shown that the sigma 1 receptor agonist activated central cholinergic functions. Therefore, we examined the effects of SA4503 on the cholinergic dysfunction-induced memory impairments in a passive avoidance task. Scopolamine, a muscarinic acetylcholine receptor antagonist, produced memory impairment, when it was administered 30 min before the training session of the passive avoidance task in rats. Single administration of SA4503 significantly reduced the scopolamine-induced memory impairment. In addition, the lesioning by injection of alpha-amino-3-hydroxy-5-isoxazole acetic acid (ibotenic acid) into the basal forebrain area produced memory impairment in rats. Repeated administration of SA4503 after lesioning of the basal forebrain area ameliorated the basal forebrain lesion-induced memory impairment. Moreover, the ameliorating effect of SA4503 against the scopolamine-induced memory impairment was antagonized by both 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-buta none (haloperidol), a sigma receptor antagonist, and N,N-dipropyl-2- [4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100), a putative sigma 1 receptor antagonist. These results suggest that SA4503 has an anti-amnesic effect against cholinergic dysfunction-induced memory impairment, and that the effect of SA4503 is mediated by the sigma 1 receptor subtype.
Senda
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Central Research Laboratories, Santen Pharmaceutical Co. Ltd., Osaka, Japan.
Matsuno
K
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Okamoto
K
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Kobayashi
T
T
Nakata
K
K
Mita
S
S
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D006168:Guinea Pigs; D007051:Ibotenic Acid; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology; D018697:Nootropic Agents / Q000378:metabolism / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects; D010423:Pentazocine / Q000627:therapeutic use; D010879:Piperazines / Q000378:metabolism / Q000627:therapeutic use*; D016548:Prosencephalon; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D012601:Scopolamine; D013619:Tacrine / Q000627:therapeutic use
D018697:Nootropic Agents; D010879:Piperazines; D017480:Receptors, sigma; D007051:Ibotenic Acid; D013619:Tacrine; C101789:SA 4503; D012601:Scopolamine; D010423:Pentazocine