The Bulky N(6) Substituent of Cabergoline Is Responsible for Agonism of This Drug at 5-Hydroxytryptamine (5-HT)_2A and 5-HT_2B Receptors and Thus Is a Determinant of Valvular Heart Disease

Abstract

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

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

“…Recent research by our group showed that 5-HT and cabergoline, another ergot alkaloid derivative, increased ERK1/2 phosphorylation in porcine aortic and mitral VICs (Kekewska et al, 2011). The present study demonstrates that terguride did not stimulate the formation of pERK1/2 but inhibited pERK1/2 activation induced by 5-HT.…”

“…The present study demonstrates that terguride did not stimulate the formation of pERK1/2 but inhibited pERK1/2 activation induced by 5-HT. The stimulatory effect of 5-HT on pERK1/2 in human, canine, and porcine VICs is susceptible to blockade by selective 5-HT 2A receptor antagonists (Connolly et al, 2009;Kekewska et al, 2011). This argues for a role of the 5-HT 2A receptor in the inhibitory effect of terguride on pERK1/2 activation by 5-HT.…”

“…5-HT 2A receptor-mediated responses were examined in endothelium-denuded porcine coronary arteries by measurement of vasoconstriction (Görnemann et al, 2008;Kekewska et al, 2011). 5-HT 2B receptor-mediated responses were investigated in porcine pulmonary arteries by measurement of endothelium-dependent relaxation (Görnemann et al, 2008;Kekewska et al, 2011). Furthermore, studies on the kinetics of terguride were performed in porcine pulmonary arteries.…”

“…In the present study, the main metabolites of terguride, such as NЉ-monodeethylterguride and N(6)-demethylterguride (6-norterguride), were also included in our analysis to assess the potential contribution of such metabolites in the interaction with 5-HT 2A and 5-HT 2B receptors. 5-HT 2A receptor-mediated responses were examined in endothelium-denuded porcine coronary arteries by measurement of vasoconstriction (Görnemann et al, 2008;Kekewska et al, 2011). 5-HT 2B receptor-mediated responses were investigated in porcine pulmonary arteries by measurement of endothelium-dependent relaxation (Görnemann et al, 2008;Kekewska et al, 2011).…”

Modulation of indole ring annulation in ergoline template: chemistry, receptor binding and in vivo pharmacology with 6-OHDA model of Parkinson’s disease

“…Various chemical modifications and synthetic variations of ergot alkaloids have been carried to reveal novel compounds retaining potent dopaminergic activity (Dosa et al, 2013;Kekewska et al, 2011;Gornemann et al, 2008). Earlier, octahydropyridocarbazoles were synthesized by modulating the apomorphine template, where the catechol ring of apomorphine was replaced by the indole ring (A and B) of ergoline, and however, did not show promising activity (Mehta et al, 1991).…”