Synthesis and comparison of some cardiovascular properties of the stereoisomers of labetalol.
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 DC spectra and confirmed by X-ray analysis. The alpha- and beta 1-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 beta 1-blocking activity elicited by labetalol and displays little alpha-blocking activity. In contrast, the S,R isomer, 3a, has most of the alpha-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 beta-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, beta-adrenergic blockade, beta-adrenergic mediated vasodilatation, and alpha-adrenergic blockade, whereas the antihypertensive activity of 2a derives from the first two mechanisms only.
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D004983:Ethanolamines / Q000138:chemical synthesis*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007741:Labetalol / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D004983:Ethanolamines; D007741:Labetalol