Fibrotic valvular heart disease (VHD) has been observed in patients with Parkinson's disease treated with dopamine receptor agonists such as pergolide and cabergoline. 5-Hydroxytryptamine 2B receptor (5-HT 2B R) agonism is the most likely cause, but other 5-HT receptors may also play a role in VHD. We aimed at characterizing the molecular fragment of cabergoline responsible for agonism at 5-HT 2B R and 5-HT 2A R. Cabergoline with an allyl substituent at N(6) behaved as a potent 5-HT 2B R full agonist in relaxation of porcine pulmonary arteries and as a weaker 5-HT 2A R partial agonist in contraction of coronary arteries. The same was true for cabergoline derivatives with cyclopropylmethyl, propyl, or ethyl at N(6). However, agonism was converted into antagonism, when the N(6) substituent was methyl. 6-Methylcabergoline retained agonism compared with cabergoline at human dopamine D 2LONG and human dopamine D

Serotonin (5-hydroxytryptamine; 5-HT) is involved in heart valve tissue fibrosis, pulmonary arterial fibrosis, and pulmonary hypertension. We aimed at characterizing the antiserotonergic properties of the ergot alkaloid derivative terguride [1,1-diethyl-3-(6-methyl-8␣-ergolinyl)urea] by using functional receptor assays and valvular interstitial cell culture. Terguride showed no vasoconstrictor effect in porcine coronary arteries (5-HT 2A receptor bioassay) and no relaxant effect in porcine pulmonary arteries (5-HT 2B receptor bioassay). Terguride behaved as a potent antagonist at 5-HT 2A receptors (noncompetitive antagonist parameter pDЈ 2 9.43) and 5-HT 2B receptors (apparent pA 2 8.87). Metabolites of terguride (NЉ-monodeethylterguride and 6-norterguride) lacked agonism at both sites. NЉ-monodeethylterguride and 6-norterguride were surmountable antagonists at 5-HT 2A receptors (pA 2 7.82 and 7.85, respectively) and 5-HT 2B receptors (pA 2 7.30 and 7.11, respectively). Kinetic studies on the effects of terguride in pulmonary arteries showed that the rate to reach drug-receptor equilibrium for terguride was fast. Washout experiments showed that terguride easily disappeared from the receptor biophase. Pretreatment with terguride inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC 50 16 nM). In porcine valvular interstitial cells, 5-HT-induced activation of extracellular signal-regulated kinase (ERK) 1/2, an initiator of cellular proliferation and activity, was blocked by terguride as shown by Western blotting. In these cells, the stimulatory effect of 5-HT on [3 H]proline incorporation (index of extracellular matrix collagen) was blocked by terguride. Because of the inhibition of both 5-HT 2A and 5-HT 2B receptors, platelet aggregation, and cellular proliferation and activity (ERK1/2 phosphorylation and collagen production) terguride may have therapeutic potential in the treatment of fibrotic disorders.

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