Effects of structure-activity relationships of alpha-adrenergic compounds on electrolyte transport in the rabbit ileum and rat colon.

Clonidine, an alpha 2-adrenergic agonist, increases electrolyte absorption in the intestine and inhibits diarrhea. In an attempt to develop a gut-specific alpha 2-adrenergic compound for the treatment of diarrhea, we tested several imidazoline derivatives to determine which aspects of the molecule are gut specific. The potency of each compound in the stimulation of electrolyte transport in the rabbit ileum and rat colon was determined using a modified Ussing chamber technique. These results were then compared with the ability of these drugs to lower blood pressure following intracisternal injection in spontaneously hypertensive rats, as well as with other alpha 2-adrenergic properties that have been defined in previous studies. Results indicate that all imidazoline derivatives interact with alpha 2-adrenergic receptors in the gut preparation but activate the ion transport processes to a variable extent; i.e., all analogs tested are either agonist or antagonist for ion transport. Structure activity relationships were derived; for the agonist property in the gut, the imidazoline derivative required (a) substitution (in order of potency) with halide greater than CH3 or C2H5 greater than CH3O or greater than OH at position 2 or 6 of the phenyl ring, or a simultaneous substitution at positions 3 and 4 with hydroxy groups, or certain other groups that independently enhance the agonist properties and (b) the presence of a proper bridging unit between the phenyl and imidazoline rings, NH greater than or equal to CH2. In addition, it was found that certain compounds with a methoxy substitution of the phenyl ring displayed a dissociation between the intestinal ion transport potency and central hypotensive activities. 2-Methoxytolazoline, which was relatively active in the gut as compared with other methoxy-substituted compounds, had little effect in lowering blood pressure. However, 3,5- or 2,5-dimethoxytolazoline had no effect on intestinal ion transport but lowered blood pressure in spontaneous hypertensive rats. These results indicate that the alpha 2-adrenergic receptors in the gut and brain may be different. Further modification of the imidazoline molecule could result in analogs with selective ion transport action in the intestine.