Neurochemical profile of EMD 45609 (carmoxirole), a dopamine DA₂-receptor agonist

Summary

A new potential antihypertensive drug, EMD 45609 (carmoxirole), has been characterized in various in vivo and in vitro models. EMD 45609 displayed high affinity for dopamine D₂-receptors combined with negligible binding to D₁-receptors in binding assays in vitro. However, in tests in vivo for central D₂-receptor activity, EMD 45609 exhibited only weak activity. Thus, after p. o. administration, striatal LrDOPA accumulation in intact rats was unchanged up to 100 mg/kg p. o., i.e. doses 100 times higher than those reported to induce depressor activity. Central dopamine agonistic activity could only be verified in the more sensitive model of the reserpinized rat. EMD 45609 was more than 30 times less potent, however, than LY 141865 in reserpinized rats after s. c. administration. Similarly, in rats with 6-hydroxydopamine induced unilateral lesions of the substantia nigra, EMD 45609 was only marginally active. The shallow dose response curves and the submaximal effects obtained for central dopaminergic activity, as reflected in the inhibition of striatal LrDOPA accumulation, suggest that EMD 45609 is a partial dopamine D₂-receptor agonist and in addition, owing to its ionizable structure, passes less readily into the brain than several reference compounds. A marked affinity was found towards 5-HT_1A-receptors in vitro, whereas affinity for α₁- and α₂-adrenoceptors was low; accordingly, central α₂-adrenoceptor activity was not detected as EMD 45609 failed to affect hypothalamic L-DOPA accumulation even at 100 mg/kg s. c. In accordance with its high affinity for D₂-receptors in vitro, EMD 45609 inhibited field stimulated noradrenaline release from rabbit ear arteries in nanomolar threshold concentrations at 0.5 Hz. The inhibition could be completely blocked by (−)sulpiride. A biphasic concentration-response curve, however, was obtained with a maximal inhibition of ∼ 50070 at 10–100 nmol/l EMD 45609 and 0.5 Hz. At 2 Hz, inhibition was greatly attenuated at the lower concentrations and at 1 µmol/l, noradrenaline release was increased by ∼60%, but only a slightly higher increase was observed in the presence of (−)sulpiride. Further interaction studies with (−)sulpiride failed to reveal substantial α₂-adrenoceptor antagonistic actions in this preparation since only slight increases of noradrenaline release above controls were noted at 0.5 Hz and 2 Hz for 1 μmol/l and 100 nmol/l EMD 45609, respectively. Thus, the complex concentration-response curves and the frequency dependence in the rabbit ear artery are probably best explained by a partial dopamine DA₂-agonistic activity of EMD 45609 in combination with slight α₂-adrenoceptor antagonistic actions at higher concentrations.