Mitsuo Egawa

Synthesis of porcine leumorphin and some of its biological activities

The carboxy-terminal nonacosapeptide sequence of porcine preproenkephalin B contains the sequence of Leu-enkephalin at its amino terminus. The endogenous existence of this peptide, leumorphin, has not yet been proved. Synthesis of leumorphin was carried out by a solid-phase technique and the purity and structure of the synthetic peptide were confirmed. Synthetic porcine leumorphin exhibited a dose-dependent opiate effect (ED50 4.70 X 10(-9) M) on electrically stimulated contraction of the guinea pig ileum preparation. The potency was about 100 times as high as that of Leu-enkephalin. Leumorphin was less potent than dynorphin(1-13) (ED50 0.38 X 10(-9) M) but it was more active than beta h-endorphin (ED50 18 X 10(-9) M). The opiate activity was only partially reversed by naloxone. Intracisternal injection of synthetic leumorphin caused significant analgesia in mice (ED50 7.31 nmol/mouse). The potency was lower than that of beta h-endorphin (ED50 0.60 nmol/mouse) but higher than that of dynorphin(1-13) (ED50 16.10 nmol/mouse). Intracisternally injected leumorphin did not produce such a violent behavioral effect as did dynorphin(1-13), and it exhibited a mild sedative effect. The data supports the concept that leumorphin is a new type of opioid peptide and that the synthetic preparation will be useful for further biological and immunological studies on this peptide.

Effects of a novel compound MCI-225 on impaired learning and memory in rats.

Effects of MCI-225, [4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine monohydrate hydrochloride] on experimental amnesia were studied in rats and compared with those of THA [9-amino-1,2,3,4-tetrahydroacridine]. In the Morris-type water maze task, MCI-225 (1-10 mg/kg, PO) reduced the spatial learning impairment induced by scopolamine (0.5 mg/kg, IP). In a passive avoidance (PA) task, administration of MCI-225 prior to training (1-30 mg/kg, PO) lessened the carbon dioxide (CO2)-induced amnesia in a dose-dependent manner. MCI-225 (1-100 mg/kg) did not affect gross behavior. THA (0.1-3 mg/kg, PO) reduced scopolamine-induced learning deficits in the water maze task, but the effect was not significant. THA (0.3-3 mg/kg, PO) also ameliorated the CO2-induced amnesia, although slightly, in the PA task. THA (10 mg/kg, PO) increased locomotor activity and higher dose of THA (30 mg/kg, PO) induced tremor, hypersalivation, and muscle relaxation. These results suggest that MCI-225 lessens impairments in learning and memory without causing serious behavioral abnormalities.

Effects of MCI-225 on memory and glucose utilization in basal forebrain-lesioned rats.

The effects of MCI-225 on amnesia, the cerebral glucose metabolism, and choline acetyltransferase (ChAT) activity in basal forebrain (BF)-lesioned rats were studied in comparison with those of tacrine. Bilateral BF lesions with ibotenic acid impaired the performance in passive avoidance (PA) tasks. Single administration of MCI-225 (10 mg/kg, PO) after a 2-week postoperative recovery period, increased the escape latencies in the PA task, but was not statistically significant. Repeated administration of MCI-225 (0.3 and 1 mg/kg, PO for 6 days) significantly reversed the PA failure. The BF-lesioned rat exhibited a marked decrease in the local cerebral glucose utilization (LCGU) in the frontal cortex, parietal cortex, and caudate-putamen. MCI-225 (1 mg/kg, PO for 5 days) significantly ameliorated the reduction of the LCGU in the parietal cortex. MCI-225 did not change the decrease in the cortical ChAT activity induced by the BF lesion. Repeated administration of tacrine reversed the PA failure (0.3 mg/kg, PO) but failed to prevent the decrement in the LCGU and the ChAT activity. These results suggest that MCI-225 could be effective in the treatment of senile dementia of the Alzheimer type, which is accompanied with both deficit in the BF-cortex cholinergic neuron and cerebral glucose hypometabolism.

MCI-225, A Novel Thienopyrimidine Analog, Enhances Attentional Eye Tracking in Midpontine Pretrigeminal Preparation

The effects of MCI-225, a novel psychoactive compound, and reference drugs on attention behavior were studied using visual stimulus induced vertical eye tracking movements in midpontine pretrigeminal (PTG) feline preparation. Surgery was performed under ether anesthesia and subsequently switched to nitrous oxide-fluothane which was discontinued only during experimental sessions. In addition xylocaine was locally injected. Vertical eye movements were monitored by electrooculogram (EOG) and a TV camera. To compare the effects of drugs on eye movement, numbers of spontaneous and tracking eye movements exceeding a present amplitude in EOG were counted before and during the visual stimulation, respectively. MCI-225 (1 and 3 mg/kg, i.v.) enhanced tracking movements dose-dependently without an increase in spontaneous eye movements. No or little change of the electrocorticogram (ECoG) was seen with 1 mg/kg MCI-225 and a slight increase in low voltage fast pattern was observed with 3 mg/kg, i.v.. On the other hand, tacrine (0.3 mg/kg, i.v.), physostigmine (0.03 mg/kg, i.v.) and methylphenidate (0.3 mg/kg, i.v.) enhanced both types of eye movement and induced ECoG arousal. Desipramine (3 mg/kg, i.v.) slightly increased spontaneous eye movement without affecting tracking movements. Piracetam (100 mg/kg, i.v.) decreased spontaneous eye movements only. These data clearly show that MCI-225 enhances attention to a moving object and suggest that MCI-225 could be useful in the treatment of attentional deficits and related cognitive dysfunctions in psychiatric disorders.