Proterguride, a highly potent dopamine receptor agonist promising for transdermal administration in Parkinson's disease: Interactions with α1-, 5-HT2- and H1-receptors

Dopamine receptor agonists play an important role in the treatment of Parkinson's disease and hyperprolactinemic conditions. Proterguride (n-propyldihydrolisuride) was already reported to be a highly potent dopamine receptor agonist, thus its action at different non-dopaminergic monoamine receptors, α1A/1B/1D, 5-HT2A/2B- and histamine H1, was investigated using different functional in vitro assays. The drug behaved as an antagonist at α1-adrenoceptors without the ability to discriminate between the subtypes (pA2 values: α1A 7.31; α1B 7.37; α1D 7.35) and showed antagonistic properties at the histamine H1 receptor. In contrast, at serotonergic receptors (5-HT2A, 5-HT2B) proterguride acted as a partial agonist. The drug stimulated 5-HT2A receptors of rat tail artery in lower concentrations than 5-HT itself but failed to evoke comparable efficacy (proterguride: pEC50 8.34, Emax 53% related to the maximum response to 5-HT; 5-HT: pEC50 7.03). Agonism at 5-HT2B receptors is presently considered to be involved in drug-induced valvular heart disease. Activation of 5-HT2B receptors in porcine pulmonary arteries by proterguride (pEC50 7.13, Emax 49%; Emax (5-HT) 69%), however, occurred at concentrations much higher than plasma concentrations achieving dopaminergic efficacy in humans. The results are discussed focussing on the relevance of action at 5-HT2B receptors as well as their significance for a transdermal administration of proterguride. Since it is well accepted that pulsatile dopaminergic stimulation is associated with treatment-related motor complications in the dopaminergic therapy of Parkinson's disease, the transdermal route of administration is of great clinical interest due to the possibility to achieve constant plasma concentrations.