Zusammenfassung
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) ...
Zusammenfassung
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 [H-3]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.
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