Synthesis and Comparison of Some Cardiovascular Properties of the Stereoisomers of Labetalol

Article abstract of DOI:10.1021/jm00353a017

A useful method for the separation of labetalol into its two racemic diastereomers, as well as a stereoselective synthesis of its four stereoisomers, is described.The absolute stereochemistry of each isomer was determined by analysis of the CD spectra and confirmed by X-ray analysis.The α- and β₁-adrenergic blocking properties, as well as the relative antihypertensive activities, have been measured in rats.The R,R isomer, 2a (SCH 19927), possesses virtually all of the β₁-blocking activity elicited by labetalol and displays little α-blocking activity.In contrast, the S,R isomer, 3a, has most of the α-blocking activity.Of the four isomers, only 2a has antihypertensive potency comparable to that of labetalol.These findings, coupled with published data showing that labetalol possesses β-adrenergic mediated peripheral vasodilating activity deriving essentially from its R,R isomer, lead to the following conclusion: The antihypertensive activity of labetalol can be ascribed to at least three identified complementary mechanisms, β-adrenergic blockade, β-adrenergic mediated vasodilatation, and α-adrenergic blockade, whereas the antihypertensive activity of 2a derives from the first two mechanisms only.