Interactions of dimethoxy-substituted tolazoline derivatives with alpha 1- and alpha 2-adrenoreceptors in vitro.

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)