RT Journal Article SR Electronic T1 The bulky N(6) substituent of cabergoline is responsible for agonism of this drug at serotonin 5-HT2A and 5-HT2B receptors and thus a determinant of valvular heart disease JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.111.181255 DO 10.1124/jpet.111.181255 A1 Alexandra Kekewska A1 Harald Hubner A1 Peter Gmeiner A1 Heinz H. Pertz YR 2011 UL http://jpet.aspetjournals.org/content/early/2011/04/25/jpet.111.181255.abstract AB 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-hydroxytryptamine2B receptor (5-HT2BR) agonism is the most likely cause but other 5-HTRs may also play a role in VHD. We aimed at characterizing the molecular fragment of cabergoline being responsible for agonism at 5-HT2B and 5-HT2ARs. Cabergoline with an allyl substituent at N(6) behaved as a potent 5-HT2BR full agonist in relaxation of porcine pulmonary arteries and as a weaker 5-HT2AR 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 to cabergoline at human hD2L and hD2SRs as determined by [35S]GTPĪ³S binding. In porcine aortic valve cusps, 5-HT-induced contractions were inhibited by ketanserin (5-HT2A/2CR antagonist) but not by SB204741 (5-HT2BR antagonist). In porcine valvular interstitial cells, cabergoline-induced activation of ERK1/2, an initiator of cellular proliferation and activity, was blocked by MDL100907 (5-HT2AR antagonist) and GR127935 (5-HT1BR antagonist), whereas the stimulatory effect on 3H-proline and 3H-glucosamine incorporations (indices of extracellular matrix collagen and glycosaminoglycan) was blocked by MDL100907. We conclude that the bulky N(6) substituent of cabergoline is responsible for 5-HT2A and 5-HT2BR agonism. The increased ERK1/2 phosphorylation and production of extracellular matrix by cabergoline are mediated by 5-HT2ARs. However, the moderate potency of cabergoline at native 5-HT2ARs suggests that these are not the preferential target in VHD in vivo.