A new dopamine agonist in dopamine deprived systems: FCE 23884

Abstract

FCE 23884, a newly synthesized ergoline-derivative, shows a unique pharmacological profile, displaying a full dopamine (DA) antagonism in normal animals but a full DA agonism indenervated animal models. In normal animals FCE 23884, administered by different routes, showed a variety of pharmacological effects similar to those seen with standard DA antagonists (Table 1). In fact the compound potently, dose-dependently, antagonized the apomorphine-induced climbing behaviour in mice, the apomorphine-induced yawning in rats and the amphetamine-induced toxicity in grouped mice. The compound depressed per s~ spontaneous locomotor activity in both mice and rats, impaired the Sidman's avoidance in rats and completely antagonized apomorphine-induced emesis in Beagle dogs. The above reported results are all compatible with the antidopaminergic properties displayed by antipsychotic agents (Worms et al., 1983) and support that FCE 23884 acts mainly as a central D-2 antagonist in normal animals. On the contrary, in denervated animals, FCE 23884 behaves as a strong DA-ergic agent (Table 2). The compound stimulated the contralateral turning behavior in 6-OHDA lesioned rats. This effect was almost completely antagonized (81%) by the selective DI receptor antagonist SCH 23390, but slightly affected by the selective D--2 antagonist l-sulpiride. These results indicate that FCE 23884, in this context, stimulates motor activity mainly via DI receptors. In an experimental Parkinson's model, i.e. in MPTPtreated monkeys showing severe parkinsunian symptoms, FCE 23884 completely reversed the MPTPinduced akinesia and restored normal behavior. In reserpinized mice FCE 23884 reversed the induced akinesia restoring the locomotor activity. Taken as a whole, these results strongly support that FCE 23884 exerts a potent DA agonist activity in DA deprived animals. To better understand the relevance of the DA presence for FCE 23884 antagonist/agonist activity, the model of rcserpinized mice was chosen because of the reproducibility of DA depletion and the absence of the DA receptors supersensitivity (Liberini et al., 1989). Interaction studies with the DA precursor LDOPA and with the mixed or selective DI /D-2 direct agonists were performed in the model of the locomotor recovery in reserpinized mice.