| Abstract
| - A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and related analogues wereprepared and evaluated for their bradycardic activities in isolated right atrium and inanesthetized rats. (±)-6,7-Dimethoxy-2-{1-[3-(3,4-methylenedioxyphenoxy)propyl]-3-piperidyl}-1,2,3,4-tetrahydroisoquinoline (4) was chosen as a lead, and structural modifications wereperformed on the tetrahydroisoquinoline ring and the terminal aromatic ring. The modificationson the tetrahydroisoquinoline ring revealed that the 1-oxo-1,2,3,4-tetrahydroisoquinoline ringsystem was optimum structure for both in vitro potency and in vivo efficacy. Furthermore,methoxy, ethoxy, and methoxycarbonyl groups were identified as preferable substituents onthe terminal aromatic ring. One of the 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives, (R)-10a, was further evaluated for its bradycardic activity and inhibitory activity against If currents.Compound (R)-10a demonstrated potent bradycardic activity in rats with minimal influenceon blood pressure after oral administration. The compound also showed inhibition of If currents(IC50 = 0.32 μM) in guinea pig pacemaker cells.
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