Pharmacological properties of a wide array of ergolines at functional alpha(1)-adrenoceptor subtypes.

Ergot alkaloids act as (partial) agonists or antagonists at serotonergic, dopaminergic and alpha-adrenergic receptors. In contrast to their affinity at serotonergic (5-HT) and dopaminergic receptor subtypes, only limited information is available concerning their interaction with alpha-adrenoceptor subtypes. This especially holds true for native alpha-adrenoceptors. Therefore, we studied the pharmacological profile of 25 ergolines at alpha(1A)-, alpha(1B)- and alpha(1D)-adrenoceptors in vascular rings or strips of rat and guinea pig endowed with these receptors. Contractile responses were studied by measurement of isometric tension changes in rat tail artery (alpha(1A), alpha(1B)), guinea pig spleen (alpha(1B)) and rat thoracic aorta (alpha(1D)). The anti-migraine drugs ergotamine and dihydroergotamine, the anti-parkinsonian drug lisuride and the anti-hyperprolactinemic drug terguride behaved as antagonists or low-efficacy partial agonists at all three alpha(1)-adrenoceptor subtypes with nanomolar receptor affinity. Derivatives of these drugs showed lower affinity at alpha(1)-adrenoceptors than the parent compounds. Each individual ergoline derivative tested showed low discriminatory capability at the subtypes, alpha(1A), alpha(1B), alpha(1D). A low discriminatory power between the subtypes (alpha(1A), alpha(1B), alpha(1D)) seems to be a class effect of the ergolines. The nanomolar affinities of ergotamine, dihydroergotamine and lisuride for alpha(1)-adrenoceptors may affect their effectiveness as anti-migraine and anti-parkinsonian drugs, respectively.

Striking differences of action of lisuride stereoisomers at histamine H1 receptors.

This study has characterised the pharmacological profile of some dopaminergic agents of the ergoline family including the antiparkinsonian drug 8S-lisuride at native guinea pig histamine H(1) receptors and recombinant human and guinea pig H(1) receptors. We used segments of guinea pig ileum to study contractile responses, Sf9 insect cell membranes expressing the guinea pig H(1) receptor (gpH(1)R) and the human H(1) receptor (hH(1)R) to analyse GTPase activity of G(q)-proteins and we conducted [(3)H]mepyramine binding studies using recombinant gpH(1)Rs and hH(1)Rs. 8S-Lisuride acted as a potent partial agonist at H(1)Rs of guinea pig ileum (pD(2) 7.6, E (max) 28% of histamine-induced maximum response) and as a silent antagonist at recombinant gpH(1)Rs (pA(2) 7.5) and hH(1)Rs (pA(2) 7.7) in GTPase studies. In contrast, its epimeric counterpart, 8R-lisuride, lacked efficacy and showed much lower affinity for H(1)Rs of both species than 8S-lisuride. High affinity of 8S-lisuride and low affinity of 8R-lisuride was also estimated for gpH(1)Rs and hH(1)Rs in radioligand binding studies. The 1-allylated derivative of 8S-lisuride, 1-allyl-8S-lisuride, was equipotent with its parent compound (pD(2) 7.7) and showed enhanced efficacy in guinea pig ileum and at recombinant gpH(1)Rs in GTPase studies (E (max) 53%, 32%). Other antiparkinsionian drugs such as 8S-terguride, pergolide, cabergoline and bromocriptine displayed lower affinities for H(1)Rs than 8S-lisuride. In conclusion, our results show that the antiparkinsonian drug 8S-lisuride is dramatically more potent than its epimeric counterpart 8R-lisuride in all assays used. 8S-Lisuride behaved as a partial agonist at gpH(1)Rs and as a silent antagonist at hH(1)Rs. Thus 8S-lisuride may act as an antagonist in vivo. This may be of potential importance since H(1)Rs modulate dopaminergic transmission in the brain.

Evaluation of the transdermal permeation behavior of Proterguride from drug in adhesive matrix patches through hairless mouse skin.

The transdermal in vitro permeation behavior of the highly potent dopamine agonist Proterguride was investigated using hairless mouse skin as a model membrane. Drug in adhesive matrix formulations based on different types of pressure-sensitive adhesives (Eudragit E 100 and Gelva7883 as acrylates, Oppanol B 15 SFN as polyisobutylene, and BioPSA 7-4202 as silicone) with a drug load of 3% by weight were manufactured. All patches were examined for drug crystallization by polarized microscopy immediately after the manufacturing process and after storage for 30 days in sealed aluminium laminate bags at ambient temperature and at 40 degrees C, respectively. Furthermore, the influence of the drug load in acrylate-based formulations onto the steady-state flux of Proterguride was examined. The Eudragit E 100 system delivered a significantly higher steady-state flux than the systems based on Oppanol B 15 SFN and also a somewhat higher steady-state flux than the Gelva-based patch. An addition of 10% by weight of the crystallization inhibitor povidone 25 did not significantly influence the steady-state flux of Proterguride from acrylate matrices. The lipophilic silicone and polyisobutylene adhesives facilitated drug crystallization within the short storage periods at both conditions, probably due to the absence of povidone 25, which was incompatible with these polymers. Varying the drug load in acrylate-based formulations led to a linear increase of the steady-state flux until the steady-state flux of Proterguride leveled off and the patches tended to drug crystallization. It was found that Gelva-based patches show good physical stability, good skin adhesion, and moderate flux values and, thus, can be evaluated as a basis for a suitable formulation for the transdermal administration of Proterguride.