title: 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)
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008750:Methyldopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D014443:Tyrosine / Q000494:pharmacology
chemical_list: C043621:2-(2,6-dichlorophenyloxy)-2-imidazoline; D000959:Antihypertensive Agents; D001381:Azepines; D007093:Imidazoles; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; C043620:methydopa (2-oxo-1,3-dioxol-4-yl)methyl ester; D014443:Tyrosine; D000068438:Brimonidine Tartrate; C036339:St 1913; D008750:Methyldopa; C032860:ICI 106270; C019494:alpha-monofluoromethyldopa; C029346:LR 99853; C043619:ST 1967; C037908:methyldopa pivaloyloxyethyl ester; C015603:azepexole; D003000:Clonidine