title: Interactions of dimethoxy-substituted tolazoline derivatives with alpha 1- and alpha 2-adrenoreceptors in vitro.
abstract: The activities of a series of dimethoxy-substituted tolazoline derivatives were investigated at alpha 1-adrenoreceptors in guinea-pig aorta and alpha 2-adrenoreceptors in field-stimulated guinea-pig ileum. Radioligand binding studies to alpha 1- and alpha 2-adrenoreceptors in rat cerebral cortex were also performed to support the pharmacological findings. The 2,5- and 3,5-dimethoxy-substituted tolazoline derivatives were potent full agonists at alpha 1-adrenoreceptors in guinea-pig aorta, whereas the 2,3- and 3,4-dimethoxy-substituted tolazoline derivatives were inactive as alpha 1-adrenoreceptor agonists. 2,3-Dimethoxytolazoline was a partial agonist at alpha 2-adrenoreceptors in field-stimulated guinea-pig ileum. The intrinsic activity of 2,3-dimethoxytolazoline was similar to that of clonidine, but less than that of UK-14,304. The -log ED50 of 2,3-dimethoxytolazoline (7.66) was only 3- to 5-fold lower than that of clonidine or UK-14,304, indicating that this compound has relatively high potency as an alpha 2-adrenoreceptor agonist. The 2,5-, 3,5- and 3,4-dimethoxy-substituted tolazoline derivatives were inactive as alpha 2-adrenoreceptor agonists. 3,4-Dimethoxytolazoline was a moderately potent and selective alpha 2-adrenoreceptor antagonist in field-stimulated guinea-pig ileum. The results indicate that the dimethoxy-substituted tolazoline derivatives possess different pharmacological activities and selectivities at alpha 1- and alpha 2-adrenoreceptors, depending upon the positions of the dimethoxy substitutions. The 2,5- and 3,5-dimethoxytolazoline derivatives are potent and selective alpha 1-adrenoreceptor agonists, whereas 2,3-dimethoxytolazoline is a potent and selective alpha 2-adrenoreceptor agonist. 3,4-dimethoxytolazoline is a moderately potent and selective alpha 2-adrenoreceptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: R R
authors.initials: RR
authors.lastname: Ruffolo
authors.forename: K
authors.initials: K
authors.lastname: Messick
authors.forename: J S
authors.initials: JS
authors.lastname: Horng
mesh_terms: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D014043:Tolazoline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D004146:Dioxanes; D007093:Imidazoles; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D000068438:Brimonidine Tartrate; D014043:Tolazoline; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine; C014282:cirazoline; D009638:Norepinephrine