SPECIES-SELECTIVE BINDING OF [H-3] IDAZOXAN TO ALPHA(2)-ADRENOCEPTORS AND NON-ADRENOCEPTOR, IMIDAZOLINE BINDING-SITES IN THE CENTRAL-NERVOUS-SYSTEM

1 We have used the imidazoline derivative [H-3]-idazoxan to define alpha2-adrenoceptors and nonadrenoceptor, imidazoline binding sites in cerebral cortex membranes of calf, mouse, rat, guinea-pig and man. 2 Competition experiments using the selective alpha-adrenoceptor drugs, rauwolscine and corynanthine, indicated that [H-3]-idazoxan bound to a single population of sites in the calf and mouse membranes. However, [H-3]-idazoxan also labelled non-adrenoceptor, imidazoline binding sites in the rat (15%), guinea-pig (30%) and human (40%) cerebral cortex membranes. 3 Competition experiments with adrenaline and cirazoline in the guinea-pig cortex, verified [H-3]-idazoxan binding to both alpha2-adrenoceptors and to non-adrenoceptor, imidazoline binding sites. 4 It has been postulated by several groups that [H-3]-idazoxan may possess partial agonist activity. To investigate this further, saturation experiments were performed in the cerebral cortex membranes of all five species in the absence and presence of 300 mum guanosine triphosphate (GTP). GTP had no effect on [H-3]-idazoxan binding in guinea-pig cerebral cortex; in both rat and mouse membranes 300 mum GTP increased the dissociation constant for [H-3]-idazoxan by 2-3 fold without significantly affecting the B(max). GTP reduced the B(max) by approximately 30% and 60% in calf and human cerebral cortex membranes, respectively, without significantly altering the K(d). 5 Saturation experiments were performed in the calf cerebral cortex membranes in the absence and presence of 300 mum GTP with the selective alpha2-adrenoceptor agonist [H-3]-clonidine and the selective muscarinic antagonist [H-3]-quinuclidinyl benzilate (QNB). GTP reduced the B(max) for [H-3]-clonidine without altering the K(d). but failed to affect either the B(max) or the K(d) for [H-3]-QNB. 6 Saturation experiments were performed in human cerebral cortex membranes in the presence of alpha2-adrenoceptor blockade with and without GTP. GTP 300 mum reduced the B(max) for [H-3]-idazoxan at the non-adrenoceptor, imidazoline binding sites, without affecting the K(d). GTP did not affect [H-3]-QNB binding to muscarinic sites. 7 Thus, there is a need to investigate further the pharmacological actions of [H-3]-idazoxan in view of its ability to recognise both alpha2-adrenoceptors and non-adrenoceptor, imidazoline binding sites and because it might possess agonist activity at some of these sites.