ABSTRACT
New oxypropanol alpha- and beta-adrenoceptor blocking agents, analogs of labetalol, were synthesised and studied in vitro in left atria and aorta for alpha and beta activity.
Subject(s)
Labetalol/chemical synthesis , Propanols/chemical synthesis , Adrenergic alpha-Antagonists/chemical synthesis , Adrenergic alpha-Antagonists/pharmacology , Adrenergic beta-Antagonists/chemical synthesis , Adrenergic beta-Antagonists/pharmacology , Animals , Aorta/drug effects , Heart Atria/drug effects , Labetalol/pharmacology , Propanols/pharmacology , RatsABSTRACT
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.
Subject(s)
Ethanolamines/chemical synthesis , Hemodynamics/drug effects , Labetalol/chemical synthesis , Adrenergic alpha-Antagonists , Adrenergic beta-Antagonists , Animals , Antihypertensive Agents , Blood Pressure/drug effects , Heart Rate/drug effects , Labetalol/pharmacology , Rats , StereoisomerismABSTRACT
A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess beta-adrenergic blocking properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked alpha-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man, and syntheses of its four stereoisomers are described. The enantiomer 90 with the R configuration at both asymmetric centers possessed most of the beta-blocking activity but little alpha-blocking activity. That with the S configuration at the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an alpha-adrenoceptor blocking agent.
