EFFECTS OF IODOPROXYFAN, A POTENT AND SELECTIVE HISTAMINE H-3 RECEPTOR ANTAGONIST, ON ALPHA(2) AND 5-HT3 RECEPTORS

We determined the affinity and/or potency of the novel H-3 receptor an tagonist iodoproxyfan at alpha(2) and 5-HT3 receptors. Iodoproxyfan an d rauwolscine (a reference alpha(2) ligand) (i) monophasically displac ed H-3-rauwolscine binding to rat brain cortex membranes (pK(i) 6.79 a nd 8.59); (ii) facilitated the electrically evoked tritium overflow fr om superfused mouse brain cortex slices preincubated with H-3-noradren aline (pEC(50) 6.46 and 7.91) and (iii) produced rightward shifts of t he concentration-response curve (CRC) of (unlabelled) noradrenaline fo r its inhibitory effect on the evoked overflow (pA(2) 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3 mu mol/l failed to evoke a c ontraction by itself but depressed the maximum of the CRC of 5-hydroxy tryptamine (pD(2)' 5.24). Tropisetron (a reference 5-HT3 antagonist) p roduced rightward shifts of the CRC of 5-hydroxytryptamine (pA(2) 7.84 ). In conclusion, the affinity/potency of iodoproxyfan at H-3 receptor s (range 8.3-9.7 [1]) exceeds that at alpha(2) receptors by at least 1 .5 log units and that at 5-HT3 receptors by at least 3 log units.