New centrally acting antihypertensive drugs related to methyldopa and clonidine.

Abstract

It has been well established that the antihypertensive drugs clonidine and methyldopa lower blood pressure by acting on postsynaptic alpha 2-adrenergic receptors within cardiovascular control centers of the brain. A number of novel agents designed as lipophilic and highly selective alpha 2-adrenergic stimulants have been synthesized and in general the pharmacological features of these agents resemble clonidine or alpha-methylnorepinephrine, the principal metabolite of methyldopa. The clonidine analogs, ICI-106,270, UK-14,304, piclonidine (LR-99,853), and the bridge analogs (ST-1913, ST-1966,ST-1967) exhibit varying activity on the central cardiovascular control centers. ICI-106,270 is of interest because relative to clonidine it appears to exert fewer CNS side effects. Azepexole (BHT-933) is also of interest because, although structurally unrelated to clonidine, it appears to interact with central alpha-adrenergic receptors in a manner similar to that of clonidine. In contrast, central administration of ST-1966, a monoatomic bridge analog of clonidine, lowers blood pressure in animals treated with an alpha 2-antagonist, which suggests other mechanisms may be involved in its action. Novel antihypertensive agents structurally similar to methyldopa have not been described, although viable pro-drugs of methyldopa such as 2-oxo-1,3-dioxol-4-yl-methyl and pivaloyloxyethyl esters have been shown to have greater oral activity than methyldopa, presumably because they are more lipophilic than the parent moiety.(ABSTRACT TRUNCATED AT 250 WORDS)