6-Methylergoline-8-carboxylic acid esters as serotonin antagonists: N1-substituent effects on 5HT2 receptor affinity

Marzoni, Gifford; Garbrecht, William L.; Fludzinski, Pawel; Cohen, Marlene L.

doi:10.1021/jm00393a024

Cited by 12 publications

(18 citation statements)

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“…5 To increase solubility of 9,10-dihydrolysergic acid (2) in organic solvents, the corresponding methyl ester 5 was prepared (Scheme 2). 6 In the next steps allylic substituent on 6-N of 5 had to be introduced. To introduce the allylic substituent on 6-N of 5, 9,10-dihydrolysergic acid (2) had to be N-demethylated rst.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Wagger¹,

Požes

Požgan

2013

RSC Adv.

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For the use of analytics, European pharmacopoeial impurities A, B, C, and D of cabergoline were synthesized. Ergocryptine was chosen as a starting material and synthesis was accomplished via two approaches, different in length and stereochemical outcome. A longer, indirect approach was realized through otherwise problematic oxidations of the 9,10-dihidrolysergol derivative, to the corresponding aldehyde and carboxylic acid. This was achieved by the use of activated DMSO and a Pinnick oxidation sequence. All four synthesized impurities are used as analytical standards in cabergoline manufacturing processes.

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Section: Resultsmentioning

confidence: 99%

“…Suspension formed, was stirred at room temperature for 2 h, aer which it was ltered, washed with H 2 O and dried to give titled compound as an off white solid (6. 25 (6). To an oven dried glassware, dried compound 5 (8.51 g, 29.9 mmol) was weighed and anhydrous DCM (200 mL) was added under N 2 atmosphere.…”

Section: Methylmentioning

confidence: 99%

Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Wagger¹,

Požes

Požgan

2013

RSC Adv.

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“…Chemistry LY53857 is the prototype in a series of 6-methylergoline-8b-carboxylic acid esters (Marzoni et al 1987;Garbrecht et al 1988) that shows potent 5-HT 2A receptor antagonist activity (Cohen et al 1983). We intended to synthesize structurally related O-acylated derivatives of 9,10-didehydro-8b-hydroxymethyl-6-methylergoline (lysergol) and O-ACYLATED DERIVATIVES OF LYSERGOL AND DIHYDROLYSERGOL-I 8b-hydroxymethyl-6-methylergoline (dihydrolysergol-I), so-called ergoline reverse esters, which share with LY53857 an isopropyl substituent at N(1) and an aliphatic branched-chain substituent at the C-8b position.…”

Section: Resultsmentioning

confidence: 99%

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Pertz

Brown

Gager

et al. 1999

Journal of Pharmacy and Pharmacology

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A series of simple O-acylated derivatives of the naturally occurring clavine alkaloids lysergol and dihydrolysergol-I were synthesized and tested in-vitro for their ability to interact with 5-HT2A receptors in rat tail artery, 5-HT2C receptors in piglet choroid plexus, 5-HT1B receptors in guinea-pig iliac artery and alpha1-adrenergic receptors in rat aorta. In contrast to the classical ergoline 5-HT2A receptor antagonists methysergide and LY53857, the compounds produced competitive antagonism of the 5-HT response in rat tail artery. Affinities of ergolines 3-14 were higher (pA2 values of 7.33-8.40) than those of the parent alcohols lysergol (1) and dihydrolysergol-I (2), respectively. The introduction of an isopropyl substituent at the N(1) position of the compounds failed to enhance 5-HT2A receptor affinity. Compounds 3-14 exhibited lower affinities for alpha1-adrenergic receptors than for 5-HT2A receptors. In particular, those lysergol derivatives that had an isopropyl substituent at the N(1) position were highly specific 5-HT2A receptor antagonists (ratio 5-HT2A/alpha1 = 302-3548). Selected derivatives of lysergol (3-5, 9-11) which were assayed for radioligand binding at 5-HT2C receptors in piglet choroid plexus had affinities that were similar to those found in rat tail artery. Additionally, lysergol and its N(1)-unsubstituted derivatives were found to be partial agonists (alpha of 0.2-0.4) for 5-HT2C receptor-mediated inositol phosphate accumulation in piglet choroid plexus. On the other hand, analogues with an isopropyl substituent at N(1) showed no measurable agonist activity. The observation that N(1)-unsubstituted derivatives of lysergol possessed agonist properties at 5-HT2C receptors whereas their agonist activity at 5-HT2A receptors was marginal (alpha of 0.05 for compound 3 at 1 microM) or not measurable, suggests that these compounds have different abilities to cause conformational change at the two receptor types. Selected derivatives of lysergol (3-5, 9-11) which were examined as ligands for 5-HT1B receptors in guinea-pig iliac artery caused insurmountable blockade of the contractile effect of 5-HT. N(1)-isopropyl derivatives had 30-50-fold lower affinities for 5-HT1B receptors of this tissue than their N(1)-unsubstituted analogues. It is concluded that O-acylated derivatives of the clavine alkaloids lysergol and dihydrolysergol-I mimic therapeutically relevant ergolines due to the complexity of their pharmacological profile as partial agonists and antagonists at 5-HT2A, 5-HT2C and 5-HT1B receptors, and at alpha1-adrenergic receptors.

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“…Previous in vitro studies using rat tissues showed markedly lower 5-HT, receptor affinity of the desisopropyl ergolines (see Fig. 1 for structures) relative to isopropyl ergolines [ Marzoni et al, 1987;Misner et al, 19901 to a greater extent than would have been predicted based on data generated using the rat 5-€IT, receptor. 5-HT, receptor antagonists have been shown to possess efficacy in animal models of thrombosis [Ashton et al, 1986[Ashton et al, , 1989Bush, 1987;Wilson et a]., 1991;Cohen et al, 1992;Herbert et al, 1993;Cushing et a]., 19931.…”

Section: Introductionmentioning

confidence: 80%

“…Efficacy of these ergolines in rabbit models of thrombosis may be due to the importance of serotonin as a mediator of platelet aggregation in this species [Killani et al, 19911. The present study was designed to compare systematically the effects of amesergide and LY215840 on rabbit platelet aggregation responses to serotonin, both in vitro and ex vivo. Further, we questioned whether the desisopropyl metabolites of amesergide and LY215840 were also antagonists of platelet 5-HT, receptors in the rabbit as has been reported at the human [Nelson et al, 19931 but riot rat [Marzoni et al, 1987;Misner et al, 19901 5-HT2 receptor.…”

Section: Introductionmentioning

confidence: 99%

Effect of 5‐HT₂ receptor antagonist ergolines and their desisopropyl metabolites on rabbit platelet aggregation in vitro and ex vivo

Cohen

Bloomquist

1994

Drug Development Research

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Amesergide and LY215840 are potent and long-lasting 5-HT2 receptor antagonists after oral administration to animals. In animals, these ergolines are metabolized t o their desisopropyl ergoline congeners which have lower affinity (40-60 nM) at 5-HT2 receptors in the rat relative to higher 5-HT2 receptor affinity (2-3 nM) at the cloned human 5-HT2 receptor. Because amesergide and LY215840 are effective in rabbit models of thrombosis, we asked whether their efficacy in the rabbit was related in part to the activity of both the parent and desisopropyl metabolites at rabbit platelet 5-HT2 receptors. Platelet aggregation responses were first optimized to ADP and the combination of ADP and serotonin with regard to platelet number (300,000 platelets/pI of plasma) and time (70 to 140 min after platelet harvest). In ex vivo studies, both amesergide and LY215840 (3.0 mg/kg p.0.) showed similar and marked antagonism of rabbit platelet 5-HT2 receptors at 1 and 24 h after their oral administration to rabbits. Furthermore, the desisopropyl ergoline metabolites of both amesergide and LY215840 inhibited serotonin-amplified platelet aggregation responses in vitro as did amesergide and LY215840. Thus, these studies add support to the hypothesis that the desisopropyl metabolites of amesergide and LY215840 may contribute to the oral antithrombotic efficacy of the parent molecules in rabbits. o

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6-Methylergoline-8-carboxylic acid esters as serotonin antagonists: N1-substituent effects on 5HT2 receptor affinity

Cited by 12 publications

References 1 publication

Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Effect of 5‐HT₂ receptor antagonist ergolines and their desisopropyl metabolites on rabbit platelet aggregation in vitro and ex vivo

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6-Methylergoline-8-carboxylic acid esters as serotonin antagonists: N1-substituent effects on 5HT2 receptor affinity

Cited by 12 publications

References 1 publication

Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Simple O-Acylated Derivatives of Lysergol and Dihydrolysergol-I: Synthesis and Interaction with 5-HT2A, 5-HT2C and 5-HT1B Receptors, and α1 Adrenergic Receptors

Effect of 5‐HT2 receptor antagonist ergolines and their desisopropyl metabolites on rabbit platelet aggregation in vitro and ex vivo

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Effect of 5‐HT₂ receptor antagonist ergolines and their desisopropyl metabolites on rabbit platelet aggregation in vitro and ex vivo