Synthesis of Novel Analogs of Cabergoline: Improving Cardiovascular Safety by Removing 5-HT_2B Receptor Agonism

Abstract

The dopamine agonist cabergoline has been used to treat prolactinomas, Parkinson’s disease, Cushing’s disease and sexual dysfunction. However, its clinical use was severely curtailed when it was found that patients taking cabergoline had an increased risk of developing cardiac-valve regurgitation. This potentially life-threatening condition has been associated with drugs, such as cabergoline, that are 5-HT2B receptor agonists. We prepared analogs of cabergoline and have identified several that have limited or no agonism at the 5-HT2B receptor.

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

“…Disruption of this interaction by receptor mutagenesis interferes with 5-HT receptor activation by ergot alkaloids [ 29 ]. Similarly, alkylation of ergot derivatives at the N1 position also can cause decreased receptor activation yielding compounds that act as 5-HT receptor antagonists [ 30 ]. Therefore, this structural feature of the bipolarizing ergot compounds suggests they work through serotonergic blockade.…”

“…Our data, revealing an ergomimetic quality to PZQ action, provide impetus for considering ergot alkaloids as potential drug leads for manipulating bioaminergic GpCRs to provide next generation antischistosomals [ 51 ]. Ergot alkaloids have been used clinically in a range of applications (migraine, obstetrics, Parkinson’s disease, diabetes), although owing to their broad GpCR binding profile they are often written off as problematic, ‘dirty’ compounds [ 30 ] and therefore often deliberately excluded from drug screens. However, this may be an oversight in the context of parasitic chemotherapy.…”

Role of “old” pharmacological agents in the treatment of Cushing’s syndrome

“…Surveillance is recommended for the risk of cardiac valve regurgitation, anyhow low [ 53 ]. Novel cabergoline analogues are being developed aimed at improving cardiovascular safety [ 54 ].…”

Crystal structure ofrac-3-[2,3-bis(phenylsulfanyl)-3H-indol-3-yl]propanoic acid

“…1], have been long known to exhibit various pharmacological activities (Hofmann, 1978). Examples include pergolide (Gilbert et al, 2000), bromocriptine (Weber et al, 1981), and cabergoline (Dosa et al, 2013), which have been used as treatments for Tourette's syndrome, psoriasis, and Parkinson's disease, respectively. Uhle's ketone (3) is a commonly used intermediate in the synthesis of some ergot alkaloids (Moldvai et al, 2004;Uhle, 1951).…”