Abstract

Cardiac-valve regurgitation observed in Parkinson patients treated with the ergoline dopamine receptor agonist 8β-methylthiomethyl-6-propylergoline (pergolide) has been associated with the agonist efficacy of the drug at 5-hydroxytryptamine_2B (5-HT_2B) receptors. 5-HT_2A receptors may also play a role in pergolide-induced cardiac-valve regurgitation. We studied the pharmacological profile of pergolide and eight derivatives in porcine vascular rings endowed with 5-HT_2B and 5-HT_2A receptors to detect the molecular fragment of the pergolide molecule that may be responsible for agonism at these receptors. Pergolide derivatives showed a different substitution pattern at N(6), and the side chain at C(8) was modified by replacement of the sulfur against an oxygen atom. We demonstrate that the potent agonism of pergolide both at 5-HT_2B and 5-HT_2A receptors is retained when the N(6) propyl substituent is replaced by ethyl. However, agonism can be converted into antagonism if N(6) propyl is replaced by methyl. The N(6)-unsubstituted derivative was a low efficacy 5-HT_2B receptor partial agonist and a 5-HT_2A receptor antagonist. This pharmacological pattern was also applicable for pergolide congeners with an oxygen in the side chain at C(8). 6-Methylpergolide retained agonist efficacy and potency compared with pergolide at human (h) D_2LONG(L) and hD_2SHORT(S) receptors as determined by guanosine 5′-O-(3-[³⁵S]thio)triphosphate binding. Based on the ability of pergolide to produce potent agonism at 5-HT_2B receptors and the failure of 6-methylpergolide to act as an agonist but as a potent antagonist, we conclude that the N(6) propyl substituent of pergolide is crucial for 5-HT_2B receptor agonism and thus a determinant of valvular regurgitation.