Antiserotonergic Properties of Terguride in Blood Vessels, Platelets, and Valvular Interstitial Cells

Abstract

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.

Pharmacological Profile of 2-Bromoterguride at Human Dopamine D2, Porcine Serotonin 5-Hydroxytryptamine 2A, and α2C-Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats

“…The effects of terguride, the parent drug of these compounds, at D 2 , 5-HT 2A , a 2C , and H 1 receptors were fully in agreement with those reported by others (NewmanTancredi et al, 2002a,b;Pertz et al, 2006;Kekewska et al, 2012).…”

Serotonin inhibits apoptosis of pulmonary artery smooth muscle cells through 5-HT2Areceptors involved in the pulmonary artery remodeling of pulmonary artery hypertension

“…ERK1/2 is one of the downstream signaling targets of 5-HT 2A receptors [27][28][29]. By binding to 5-HT 2A receptors, 5-HT can phosphorylate ERK1/2, stimulates PASMC contraction [30].…”

Investigation of the relationship between ergocristinine and vascular receptors

“…Recent studies have suggested potential bioactivity of the S -epimers [13] , [14] , [15] . Previous S -epimers of non ergopeptine alkaloids have demonstrated biological activity [16] , [17] . An ergoline ergot alkaloid, 8S-lisuride, demonstrated high affinity, and higher affinity than the corresponding epimer, to a histamine receptor [16] .…”

“…Ergot alkaloids have a high affinity for their target receptors [24] , [26] , [27] , [28] , [29] , however, previous studies have only focused on R -epimers. Limited studies have assessed S -epimer receptor interactions in vitro , however, some studies assessing non ergopeptine ergot alkaloids have demonstrated agonist, and antagonist properties with relatively high affinity to vascular receptors [17] , [30] . Since in vitro binding studies can be costly and resource consuming, in silico methods can be utilized.…”