Behavioral effects of 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-be nzodioxole HCl (MKC-242), a novel 5-HT1A-receptor agonist, were evaluated using animal models of anxiety and obsessive compulsive disorder and compared against reference compounds. MKC-242 suppressed foot shock-induced fighting behavior without loss of motor coordination in mice as the reference compounds did. The ED50 values of MKC-242, buspirone, tandospirone and diazepam were 1.7, 42, 80 and 2.0 mg/kg, p.o., respectively. The duration of the suppression of fighting by MKC-242 was longer than those of buspirone and tandospirone and comparable to that of diazepam. Similar results were also obtained with the water-lick conflict test in rats. The plasma concentration of MKC-242 in rats was much higher than the reported value of buspirone during 0.25-6 hr after oral administration. In addition, MKC-242 reduced marble burying behavior without reduction of motor activity. Fluoxetine, tandospirone and diazepam also reduced the behavior at non-sedative doses. These findings indicate that MKC-242 possesses a longer-lasting anxiolytic effect than azapirones. This might be due to the high concentration of the compound in plasma. In addition, it is also suggested that MKC-242 possesses an antiobsessional effect.
Design and Syntheses of 4-Acylaminopyridine Derivatives: Novel High Affinity Choline Uptake Enhancers. Part 2.-Various analogues of the active lead compound (I) such as (II)-(IV) are synthesized and examined for high affinity choline uptake improvement. The oxopyrrolidinyl derivative (III) displays strong potency even at low concentrations and is currently in trials for Alzheimer disease treatment. -(CHAKI, H.; YAMABE, H.; SUGANO, M.; MORITA, S.; BESSHO, T.; TABATA, R.; SAITO, K.-I.; EGAWA, M.; TOBE, A.; MORINAKA, Y.; Bioorg. Med.
Design and Syntheses of 4-Acylaminopyridine Derivatives: Novel High Affinity Choline Uptake Enhancers. Part 1.-Various N-acyl derivatives of 9-amino-1,2,3,4-tetrahydroacridine, which is used in practice as AChE inhibitor for the treatment of Alzheimer's disease, are synthesized and examined for high affinity cholin uptake. The compounds (III), (VIII), and (X) are found to improve the reduced high affinity choline uptake in the hippocampal synaptosome of rats. -(CHAKI, H.; YAMABE, H.; SUGANO, M.; MORITA, S.; BESSHO, T.; TABATA, R.; SAITO, K.-I.; EGAWA, M.; TOBE, A.; MORINAKA, Y.; Bioorg. Med.
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