TL-350, an ergoline derivative with dopamine receptor agonist properties

Intravenous and intraduodenal injection of a new ergoline derivative, TL-350, produced dose-dependent inhibition of heart rate increase produced by cardioaccelerator nerve stimulation in anesthetized cats. ID50 values of TL-350 were 0.019 and 0.047 mumol/kg after i.v. and intraduodenal injection, respectively. This inhibition was reversed by either sulpiride (0.15 mumol/kg i.v.) or haloperidol (0.13 mumol/kg i.v.) but not by yohimbine (0.14 mumol/kg i.v.). TL-350 did not change isoproterenol-induced tachycardia and hypotensive responses. TL-350 caused dose-dependent decrease of arterial blood pressure and heart rate in anesthetized cats. Haloperidol (0.13 mumol/kg i.v.) prevented the hypotensive and bradycardic effects of the compound. TL-350 also produced concentration-dependent inhibition of heart rate responses to transmural stimulation of isolated cat right atria. IC50 value was 0.026 microM. Dopaminergic antagonists, haloperidol and sulpiride, antagonized the inhibitory effect of TL-350 in in vitro experiments. TL-350 did not stimulate presynaptic alpha-2 adrenergic receptors in rat vas deferens and guinea-pig ileum. TL-350 induced rotation for 3 hr in rats with unilateral denervated caudate nucleus. The compound was 0.5 as potent as apomorphine. In [3H]dopamine binding assays using rat caudate tissue, TL-350 had approximately the same activity as apomorphine in displacing the radioligand. It was concluded that TL-350 is a selective dopamine receptor agonist without possessing alpha and beta adrenergic receptor stimulating activity.