Recent reports have raised concerns that dopamine agonist drugs, particularly cabergoline and pergolide, may be associated with cardiac valvulopathy. Dopamine agonists exert their prolactin-suppressive effect via lactotroph D2S receptors, while cardiac fibrosis appears to be mediated via 5HT2B receptors. We have assessed the receptor binding and functional effects of a range of dopamine agonists to determine their relative potencies at these two receptors.
Methods: We used D2S -human recombinant receptor expressed in HEK-293 cells and 5-HT2B human recombinant receptors expressed in CHO cells. Binding assays were performed with tritiated 7-OH-DPAT and iodinated DOI respectively. Functional assays were done assessing cyclic AMP and intracellular calcium respectively. For binding, the results are expressed as percent of control specific binding and for functional assays as percent of control specific agonist response.
Results: Functional EC50 for quinagolide, cabergoline, pergolide and bromocriptine at the two receptors are presented in Table 1. At the D2S receptor, the compounds behaved as full agonists in the model studied. At the 5HT2B receptor, bromocriptine and quinagolide behaved as partial agonists in the model studied with respective efficacy of 0.55 and 0.85 whereas cabergoline and pergolide behaved as full agonists. For both receptors, the ranking in potency of the compounds could be explained by their ranking in binding affinity.
Conclusions: Quinagolide and bromocriptine appear to be partial agonists at the 5HT2B receptor. The difference in potency between effects at D2S and 5HT2B receptors was greatest for quinagolide (approx 2100×), followed by cabergoline (290×), bromocriptine (50×) and pergolide (5×). Of the four drugs, therefore, quinagolide may have the greatest safety margin between dopaminergic and serotoninergic effects.
|EC50 at D2S (nM)||0.058||0.21||0.92||4.4|
|EC50 at 5HT2B (nM)||121||61||4.6||204|