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

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

Naunyn Schmiedebergs Arch Pharmacol

Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin (Dahlem), Germany.

Published: December 2006

AI Article Synopsis

Article Abstract

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.

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http://dx.doi.org/10.1007/s00210-006-0111-0DOI Listing

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