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

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 L-DOPA 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 L-DOPA 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-HT1A-receptors in vitro, whereas affinity for alpha 1- and alpha 2-adrenoceptors was low; accordingly, central alpha 2-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.(ABSTRACT TRUNCATED AT 250 WORDS)