Dazopride

It has recently been shown that the tachycardic response to 5‐hydroxytryptamine (5‐HT) in the anaesthetized pig, being mimicked by 5‐methoxytryptamine and renzapride and blocked by high doses of ICS 205–930, is mediated by the putative 5‐HT4 receptor. In the present investigation we have further characterized this receptor.Intravenous bolus injections of the tryptamine derivatives, 5‐HT (3, 10 and 30 μg kg−1), 5‐methoxytryptamine (3, 10 and 30 μg kg−1) and α‐methyl‐5‐hydroxytryptamine (α‐methyl‐5‐HT; 3, 10, 30 and 100 μg kg−1), resulted in dose‐dependent increases in heart rate of, respectively, 25 ± 2, 48 + 3 and 68 ± 3 beats min−1 (5‐HT; n = 35); 15 ± 1, 32 ± 2 and 57 ± 3 beats min−1 (5‐methoxytryptamine; n = 30); 6 ± 4, 18 ± 6, 34 ± 6 and 64 ± 11 beats min−1 (α‐methyl‐5‐HT; n = 3).The increases in heart rate following i.v. administration of certain substituted benzamide derivatives were genereally less marked and not dose‐dependent: 1 ± 5, 11 ± 3 and 10 ± 5 beats min−1 after 300, 1000 and 3000 μg kg−1 of metoclopramide, respectively, (n = 8); 21 ± 4, 19 ± 2 and 2 ± 2 beats min−1 after 100, 300 and 1000 μg kg−1 of cisapride, respectively, (n = 5); 6 ± 2, 14 ± 2, 37 ± 6, 43 ± 8 and 34 ± 10 beats min−1 after 10, 30, 100, 300 and 1000 μg kg−1 of zacopride, respectively, (n = 6); and 1 ± 1, 2 ± 1 and 5 ± 2 beats min−1 after 300, 1000 and 3000 μg kg−1 of dazopride, respectively, (n = 4). These drugs behaved as partial agonists, antagonizing the responses to 5‐HT and 5‐methoxytryptamine dose‐dependently.The 5‐HT3 receptor agonist 1‐phenyl‐biguanide (100, 300 and 1000 μg kg−1) induced only slight increases in heart rate of 1 ± 1, 6 ± 2 and 11 + 1 beats min−1, respectively, (n = 3). These effects were not antagonized by the selective 5‐HT3 receptor antagonist granisetron (3 mg kg−1). In addition, 1‐phenyl‐biguanide (1000 μg kg−1) did not modify the tachycardia induced by either 5‐HT‐ or 5‐methoxytryptamine.High doses (3 mg kg−1) of ICS 205–930, a 5‐HT3 receptor antagonist with an indole group and devoid of effects on porcine heart rate per se, antagonized the stimulatory effects of 5‐HT, 5‐methoxytryptamine, α‐Me‐5‐HT, metoclopramide, cisapride, zacopride, dazopride and 1‐phenyl‐biguanide. However, the 5‐HT2 receptor antagonist ketanserin (0.5 mg kg−1), the 5‐HT3 receptor antagonists granisetron (3 mg kg−1) and MDL 72222 (3 mg kg−1) and the dopamine D2 receptor antagonist domperidone (3 mg kg−1) had no antagonist activity.The above results support our contention that 5‐HT, 5‐methoxytryptamine, α‐Me‐5‐HT and the substituted benzamide derivatives increase porcine heart rate by a direct action on the cardiac pacemaker, via the activation of a putative 5‐HT4 receptor. The pharmacological profile of this novel 5‐HT receptor is similar (neurones from mouse brain colliculi and human heart) or, perhaps, even identical (guinea‐pig cholinergic neurones) to other putative 5‐HT4 receptors.

The intravenous injection of cisplatin in the ferret caused a consistent emetic (vomiting/retching) response. Emesis induced by cisplatin was abolished by the 5-hydroxytryptamine (5-HT) M-receptor antagonists ICS205-930, zacopride, dazopride and metoclopramide. The neuroleptic agents haloperidol, fluphenazine, domperidone, sulpiride and tiapride also antagonized emesis induced by cisplatin but only a proportion of the animals were completely protected and diazepam and prednisolone only reduced the intensity of the response. It is concluded that compounds used in the clinic to antagonise emesis induced by chemotherapy are effective in the ferret model. Antagonism of emesis induced by cisplatin in the ferret was most potently achieved by the use of the 5-HT M-receptor antagonists ICS205-930 and zacopride. However, an antagonism of dopamine receptors would appear relevant to the anti-emetic effects of the neuroleptic agents and may contribute to the anti-emetic effects of metoclopramide. Diazepam and prednisolone exert their modest antagonism by unknown mechanisms. The use of the 5-HT M-receptor antagonists is revealed as a novel approach to the treatment of emesis induced by cisplatin.