No abstract

ABSTRACT-The effects of adenosine and its related compounds on the cholinergic twitch response were examined in electrically stimulated guinea pig ileum. Adenosine (3 x 10-'-10-5 M) and an adenosine A1-receptor agonist N6-cyclohexyladenosine (CHA, 10-8-10-6 M) suppressed the twitch. Conversely, the A2a receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680, 10-9-10-7 M) potentiated the twitch in half the preparations examined. The A1-antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), which per se did not affect the twitch, recovered the attenuated twitch caused by CHA (10-' M) or adenosine (10-6 M) and converted it into a potentiated twitch. These results suggest the presence of adenosine A1-and A2a-receptors coupled negatively and positively, respectively, to acetylcholine release in the preparation.

ABSTRACT-The effects of [1][2]fumarate, on the loperamide or clonidine-induced delayed propulsion were determined in rats and compared with those of other gastroprokinetic agents. Administration of loperamide (0.3 mg/kg, s.c.) or clonidine (0.01 mg/kg, s.c.) induced delay of the evacuation time of the teflon ball, which had been inserted into the distal colon. The delayed evacuation was improved dose dependently by KW-5092 at 3 to 10 mg/kg (p.o.) or higher. Neostigmine at 0.3 to 3 mg/kg (p.o.) and T-1815 at 1 to 100 mg/kg (p.o.) also improved the delayed ball evacuation. These results suggest that KW-5092 stimulates the delayed colonic propulsion.

A series of (E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives was prepared, and the derivatives were demonstrated to be potent inhibitors of steroid 5 alpha-reductase in the rat prostate. The structure-activity relationships were as follows. An alpha-branched alkyl or benzyl substituent of proper size at position 1 of the indole is crucial for optimal enzyme inhibitory activity. N-Methylation of the amide NH resulted in complete loss of activity. Thus, coplanarity of the benzene ring and amide moiety is essential for such activity. Among the compounds prepared, (E)-4-(2-[[3-[1-[bis(4-fluorophenyl)methyl]indol-5-yl]-1-oxo-2- butenyl]-amino]phenoxy)butyric acid (57, KF18678) was one of the most potent compounds (rat prostate 5 alpha-reductase IC50 = 3.3 nM).