tracizoline and metizoline

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-imidazole 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 male Wistar rats. Their effect was compared to that of idazoxan, a high-affinity ligand at imidazoline I(2) binding sites, but also a potent alpha(2)-adrenoceptor antagonist. Compared to idazoxan, metrazoline exhibits a higher pK(i) for imidazoline I(2) binding sites in rat liver, while the other compounds have a slightly lower pK(i); on the other hand, the novel compounds have much lower affinity than idazoxan at alpha(2)-adrenoceptors. Idazoxan stimulated 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 sites, significantly increased drinking but failed to stimulate feeding at doses of 10-50 mg/kg. Metrazoline induced hyperphagia and water drinking at doses of 50 mg/kg or higher. Its dipsogenic effect was secondary to the hyperphagic effect, since it was not observed in rats without access to food. Benazoline significantly increased feeding only in response to 30 mg/kg, but its effect was less pronounced than that of metrazoline. Tracizoline and o-nitro-tracizoline were inactive. Following injection into the lateral cerebroventricle at doses up to 100 microgram/rat, and into the third or fourth brain ventricle at doses up to 50 microgram/rat, neither idazoxan nor metrazoline induced hyperphagia. The present results support the idea that imidazoline I(2) ligands influence feeding in rats, and suggest that their site of action is not in the central nervous system. The finding that idazoxan elicits a more potent hyperphagic effect than metrazoline and benazoline, although its affinity for imidazoline I(2) binding sites is lower than that of metrazoline and similar to that of benazoline, raises the question whether its hyperphagic effect might also be due to interaction with other receptors.

Topics: Animals; Binding Sites; Dose-Response Relationship, Drug; Drinking; Eating; Idazoxan; Imidazoles; Imidazoline Receptors; Male; Rats; Rats, Wistar; Receptors, Drug

The observation that all the attempts to characterize imidazoline (I) receptors have been carried out with non-selective or poorly selective ligands prompted us to undertaken research aimed at developing selective ligand(s). In previous work using, as a starting point, cirazoline I, a potent alpha 1-adrenergic receptor agonist that also binds to I receptors, we showed that removal of the cyclopropyl ring (2) retains high affinity for I2 receptors while reducing alpha 1-adrenergic agonist activity. However, it was felt that this residual, albeit modest, alpha 1-adrenergic agonist activity might diminish the usefulness of compound 2, and we now report on our continuing efforts in this field. Starting from compound 2, we first eliminated the alpha 1-agonist component by isosteric replacement and then, by means of conformational restrictions on compound 7, succeeded in discovering tracizoline (9) and benazoline (12). These two new ligands with high affinity (pKi value 8.74 and 9.07, respectively) and unprecedented selectivity with respect to both alpha 2- (I2/alpha 2 7,762 and 18,621) and alpha 1- (I2/alpha 1 2,344 and 2,691) adrenergic receptors, are valuable tools in the study of I receptor structure and function. In addition, the large number of derivatives studied has allowed us to establish congruent qualitative structure-activity relationships and identify some structural elements governing affinity and selectivity.

Topics: Adrenergic alpha-Agonists; Animals; Cerebral Cortex; Drug Design; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Kidney; Ligands; Male; Rabbits; Rats; Receptors, Drug; Structure-Activity Relationship; Vas Deferens