Inverse agonism at α2-adrenoceptors in native tissue

Abstract Several α 2 -adrenoceptor antagonists have inverse agonist properties in cell culture systems, usually expressing high levels or a constitutively active form of α 2 -adrenoceptors. In characterizing the binding of α 2 -adrenoceptor agonists to rat brain tissue sections, we found that conditions known to alter agonist affinity for these receptors, particularly the addition of 100 μM GTP, altered the binding of the α 2 -adrenoceptor antagonist, [ 3 H](1,4-benzodioxan-2-methoxy-2-yl)-2-imidazoline hydrochloride (RX821002). In further studies, we found that under our conditions [ 3 H]RX821002 demonstrates inverse agonist properties at α 2 -adrenoceptors. This is the first demonstration of inverse agonism at α 2 -adrenoceptors in native tissue. We found that the α 2 -adrenoceptor antagonist, (2S,12bS)1′,3′-dimethylspiro(1,3,4,5′,6,6′,7,12b-octahydro-2H-benzo(b)furo(2,3-a)quinazoline)-2,4′-pyrimidin-2′-one (MK-912), did not have clearly discernible inverse agonist properties and acted as a neutral antagonist in these studies. On the other hand, the antagonist rauwolscine actually displayed partial agonist properties in our studies. These findings indicate that the inverse agonist properties of α 2 -adrenoceptor antagonists can be demonstrated in native tissue, as well as in tissue culture, and they strengthen the idea that inverse agonist properties may be of physiological and pharmacological importance.