RX 821002 as a tool for physiological investigation of alpha(2)-adrenoceptors.

RX 821002 is the 2-methoxy congener of idazoxan. In binding and tissue studies it behaves as a selective antagonist of alpha(2)-adrenoceptors, with at least 5 times greater affinity for these receptors than any other binding site. It does not select between the different types of alpha(2)-receptor. Although this drug probably has no future as a therapeutic agent, it remains a good probe for physiological activity at alpha(2)-adrenoceptors in animal experiments. A particularly useful feature of this compound is its lack of binding at I(1) and I(2) imidazoline receptors. However, it has relatively high affinity for 5-HT(1A) receptors (at which it acts as an antagonist) and a tendency to behave as an inverse agonist at alpha(2A)-adrenoceptors in some cell culture systems. These potential drawbacks may be overcome by careful design of experiments, and the greater selectivity of RX 821002 renders it much superior to yohimbine or idazoxan as a tool for probing physiological actions at alpha(2)-receptors. It can be compared favorably with other selective antagonists such as atipamezole. In physiological studies, RX 821002 augments norepinephrine release in the frontal cortex and increases drinking behavior in rat. In rabbit, intrathecal administration of this drug enhances somatic and autonomic motor outflows, showing that tonic adrenergic descending inhibition of withdrawal reflexes and sympathetic pre-ganglionic neurons is strong in this species. The potentiation of reflexes may be considered a pro-nociceptive action. In the same model, RX 821002 antagonizes the inhibitory effects of the mu opioid fentanyl, indicating that exogenous opioids synergize with endogenously released norepinephrine in the spinal cord. Thus, the careful use of RX 821002 has revealed several aspects of the physiological activity of alpha(2)-adrenoceptors in rabbit spinal cord and rat brain. We recommend that RX 821002 and/or compounds with similar selectivity for alpha(2)-adrenoceptors (atipamezole, MK-912, RS-79948) should be used in preference to yohimbine or idazoxan in all future studies of this type.