Hyperphagic effect of novel compounds with high affinity for imidazoline I-2 binding sites

Previous studies have suggested that imidazoline I-2 receptors play a role in feeding control in rats. The effect of subcutaneous (s.c.) injections of four novel imidazoline I-2 ligands, 2-naphthalen-2yl-4,5-dihydro-1H-imidaz ole hydrochloride (benazoline), 2-styryl-4,5-dihydro-1H-imidazole oxalate ( tracizoline), o-nitro-tracizoline and o-methyl-tracizoline (metrazoline) on food intake during the light phase was now evaluated in freely feeding mal e Wistar rats. Their effect was compared to that of idazoxan, a high-affini ty ligand at imidazoline I-2 binding sites, but also a potent alpha(2)-adre noceptor antagonist. Compared to idazoxan, metrazoline exhibits a higher pK (i) for imidazoline I-2 binding sites in rat liver, while the other compoun ds have a slightly lower pK(i); on the other hand, the novel compounds have much lower affinity than idazoxan at alpha(2)-adrenoceptors. Idazoxan stim ulated drinking at a dose as low as 1 mg/kg, and evoked feeding at a higher dose (30 mg/kg). The selective alpha(2)-adrenoceptor antagonist 2-methoxy- idazoxan (RX821002), with negligible affinity at imidazoline I-2 binding si tes, significantly increased drinking but failed to stimulate feeding at do ses of 10-50 mg/kg. Metrazoline induced hyperphagia and water drinking at d oses of 50 mg/kg or higher. Its dipsogenic effect was secondary to the hype rphagic effect, since it was not observed in rats without access to food. B enazoline significantly increased feeding only in response to 30 mg/kg, but its effect was less pronounced than that of metrazoline. Tracizoline and o -niho-tracizoline were inactive. Following injection into the lateral cereb roventricle at doses up to 100 mu g/rat, and into the third or fourth brain ventricle at doses up to 50 mu g/rat, neither idazoxan nor metrazoline ind uced hyperphagia. The present results support the idea that imidazoline I-2 ligands influence feeding in rats, and suggest that their site of action i s not in the central nervous system. The finding that idazoxan elicits a mo re potent hyperphagic effect than metrazoline and benazoline, although its affinity for imidazoline I-2 binding sites is lower than that of metrazolin e and similar to that of benazoline, raises the question whether its hyperp hagic effect might also be due to interaction with other receptors. (C) 200 0 Elsevier Science B.V. All rights reserved.