Synthesis and comparison of some cardiovascular properties of the stereoisomers of labetalol

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Abstract
A useful method for the separation of labetalol into its 2 racemic diastereomers and a stereoselective synthesis of its 4 stereoisomers is described. The absolute stereochemistry of each isomer was determined by analysis of the CD [circular dichroism] spectra and confirmed by X-ray analysis. The .alpha.- and .beta.1-adrenergic blocking properties, and the relative anithypertensive activities were measured in rats. The R,R isomer, 2a (SCH 19927), possess virtually all of the .beta.1-blocking activity elicited by labetalol and displayed little .alpha.-blocking activity. The S,R isomer, 3a, had most of the .alpha.-blocking activity. Of the 4 isomers, only 2a had antihypertensive potency comparable to that of labetalol. These findings, coupled with published data showing that labetalol possesses .beta.-adrenergic mediated peripheral vasodilating activity deriving essentially from its R,R isomer, led to the following conclusion: the antihypertensive activity of labetalol can be ascribed to at least 3 identified complementary mechanisms, .beta.-adrenergic blockade, .beta.-adrenergic mediated vasodilatation and .alpha.-adrenergic blockade, while the antihypertensive activity of 2a derives from the first 2 mechanisms only.