Synthesis of novel analogs of cabergoline: Improving cardiovascular safety by removing 5-HT2B receptor agonism

Article abstract of DOI:10.1021/ml3003814

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-HT_2B receptor agonists. We prepared analogs of cabergoline and have identified several that have limited or no agonism at the 5-HT_2B receptor.

Full text of DOI:10.1021/ml3003814

Letter
pubs.acs.org/acsmedchemlett
Synthesis of Novel Analogs of Cabergoline: Improving
Cardiovascular Safety by Removing 5‑HT Receptor Agonism
2
B
,
†
†
†
‡
Peter I. Dosa,* Tim Ward, Michael A. Walters, and Suck Won Kim
†Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of
Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
‡
Department of Psychiatry, University of Minnesota Medical School, 2450 Riverside Avenue, Minneapolis, Minnesota 55454, United
States
*
S Supporting Information
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.
KEYWORDS: Cabergoline, 5-HT2B, ergot alkaloid, sexual dysfunction, dopamine agonist
1
9
abergoline is a dopamine agonist that has been used
reduced 5-HT2B agonism (Figure 1). Clinical studies showed
1
2
C
clinically to treat prolactinomas, Parkinson’s disease,
that, unlike nor-dexfenfluramine, this drug does not appear to
3
2
0
and Cushing’s disease and has been reported to have positive
cause heart-valve damage in patients.
4
,5
effects in patients suffering from depression. We became
interested in this ergot alkaloid because of its potential to treat
sexual dysfunction. Cabergoline has been used clinically to treat
patients suffering from male sexual dysfunction, especially those
6
−8
with elevated prolactin levels.
An elevated level of prolactin
is a known risk factor for sexual dysfunction, and cabergoline
lowers the level of this hormone by binding to D receptors in
2
9
the pituitary gland and inhibiting prolactin synthesis. Cabergo-
Figure 1. The antiobesity agents nor-dexfenfluramine and lorcaserin
are both potent 5-HT2C agonists, but lorcaserin is a much weaker
agonist at the 5-HT2B receptor and, unlike nor-dexfenfluramine, does
not cause heart-valve damage clinically.
10−12
line is also an agonist at the D and 5-HT receptors,
4
1A
which are believed to play important roles in regulating sexual
13−16
function in both males and females.
Unfortunately, cabergoline is also a potent agonist of the 5-
11
HT2B receptor (with a reported K of 1.2 nM) and, like other
As the connection between 5-HT2B agonists and CVR had
not yet been discovered when cabergoline was first developed,
no apparent effort was made to minimize 5-HT2B agonism at
i
5
-HT2B agonists such as nor-dexfenfluramine, is known to cause
1
7,18
cardiac-valve regurgitation (CVR) in patients.
This
21
that time. There are two strategies for removing the potential
to cause heart-valve damage from cabergoline analogs: either
their activity at the 5-HT2B receptor can be reduced, or they can
be converted from agonists into antagonists, which are not
potentially fatal complication has greatly limited the clinical
use of cabergoline, especially in indications requiring high doses
of the drug. A close analog of cabergoline without the
propensity to cause CVR could potentially be of significant
therapeutic use.
We believed that it should be possible to find safer analogs of
cabergoline using design techniques developed to ameliorate 5-
HT2B agonism in other therapeutics. Recent studies have shown
that it is indeed possible to find safer analogs of drugs that have
seen their clinical use limited due to a tendency to cause CVR.
For instance, Arena Pharmaceuticals recently received FDA
approval for the antiobesity agent lorcaserin, a 5-HT2C agonist
which is structurally related to nor-fenfluramine but with greatly
2
2,23
believed to cause CVR.
We set out to try both approaches.
We began our efforts to reduce 5-HT2B activity by replacing
the dimethylamino side chain of cabergoline with a less basic
morpholine group (compound 1 in Figure 2), as a similar
change has previously been shown to help reduce activity at 5-
Received: November 7, 2012
Accepted: December 22, 2012
Published: January 14, 2013
©
2013 American Chemical Society
254
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 2. Alternate Synthesis of Morpholino Analog 1
Figure 2. Hypothesis 1: Lowering the pK of the basic amine could
a
decrease 5-HT2B activity.
2
4
HT receptors. The synthesis of 1 proved to be more
2
problematic than expected. Most published syntheses of
cabergoline start from cabergolinic acid 2 or its methyl ester
a
2
1,25
Reagents and conditions: (a) i. NaOH, H O, methanol; ii. HCl. (b) i.
2
3, shown in Schemes 2 and 1, respectively.
However,
CH Cl , 0 °C; ii. NEt , p-toluenesulfonyl chloride, reflux. (c) NEt ,
CH Cl .
2
2
3
3
a
2
2
Scheme 1. Synthesis of Morpholino Analog of Cabergoline
radiolabeled 2,5-dimethoxy-4-iodoamphetamine, as well as in a
-HT2B functional assay using HTRF quantitation of IP1
5
accumulation. Unfortunately, the results of these assays showed
that compound 1 (K 7.1 nM in the binding assay, EC 13 nM
i
50
in the functional assay) was not significantly less active at the 5-
HT2B receptor than cabergoline (K 1.4 nM, EC 13 nM). As
i
50
expected, both compounds were full agonists at the 5-HT2B
receptor (see Figure 4 for a listing of all in vitro data and the
structures of compounds evaluated).
We then turned our efforts to finding analogs of cabergoline
that were 5-HT2B antagonists instead of agonists. We based our
initial approach on the results of a study by Pertz and co-
workers, who found that while the ergot alkaloid pergolide
(
which is 6-propyl substituted) is a functional agonist at 5-HT2B
receptors in porcine pulmonary arteries, 6-methylpergolide is a
5
27
-HT2B antagonist (Figure 3). Both compounds are full
a
Reagents and conditions: (a) Methanol, NEt . (b) 3-Morpholino-
3
propylamine, 65 °C. (c) i. Boc O, DMAP, THF; ii. NaHMDS; iii.
2
PhOCOCl. (d) i. EtNH ·HCl, 2-propanol, 50 °C; ii. HCl, H O.
2
2
extensive attempts to acquire either of these compounds
commercially were unsuccessful. Fortunately, it is possible to
synthesize 3 directly from cabergoline using the method of
Wang and co-workers, who found that simply stirring
cabergoline in methanol and triethylamine leads to the near
Figure 3. Replacing the 6-propyl group of pergolide with a methyl
group switches the functionality at the 5-HT2B receptor but not at the
D receptor.
2
26
quantitative recovery of methyl ester 3 (Scheme 1). Further
investigation showed that it was possible to bypass methyl ester
agonists at the D receptor. We therefore decided to prepare an
2
3
and instead generate amide 4 directly in one step by heating
analog of cabergoline in which the 6-allyl moiety is replaced by
a methyl group. As we were also unable to obtain the 6-methyl
analog of compound 3 commercially, we instead began our
synthesis by hydrolyzing dihydroergotamine and converting the
resulting acid into a methyl ester in order to ease purification
(Scheme 3). From methyl ester 7, hydrolysis followed by
cabergoline with 3-morpholinopropylamine (Scheme 1). An
attempt to access the desired final N-acylurea 1 directly from
21
amide 4 by heating 4 with ethyl isocyanate led to an
inseparable mixture of products. We instead used a multistep
synthetic route through Boc-protected phenyl carbamate 5 to
25
21
obtain 1 from 4 (Scheme 1). As this multistep synthesis
proved to be rather time-consuming, we later developed a faster
route to 1, by reacting cabergolinic acid (2) with the
morpholino-analog of EDC, which was prepared from 3-
morpholinopropylamine and ethyl isocyanate (Scheme 2).
Compound 1 and cabergoline were evaluated in a
competitive binding assay at the 5-HT2B receptor against 1 I-
coupling to EDC yielded the desired 6-methylated cabergo-
line analog 8.
Compound 8 demonstrated similar potency as cabergoline
and compound 1 in a 5-HT2B radioactive binding assay (K 2.2
i
nM; see Figure 4). A 5-HT2B functional assay showed that the
change from a 6-allyl group to a 6-methyl group did
significantly reduce 5-HT2B agonism but was not enough to
25
2
55
dx.doi.org/10.1021/ml3003814 | ACS Med. Chem. Lett. 2013, 4, 254−258

ACS Medicinal Chemistry Letters
Letter
a
Scheme 3. Synthesis of 6-Methylcabergoline
yield to furnish 10 (Scheme 4). This primary amine was then
converted into an aldehyde using a biomimetic procedure
32
developed by Rapoport. First the amine was condensed with
-formyl-1-methylpyridinium benzenesulfonate to form a
4
Schiff-base intermediate. The resulting imine was then
deprotonated with DBU to form an anion (with resonance
structures 11a and 11b). Next, protonation with oxalic acid
occurred preferentially on the carbon closer to the highly
32
electron-withdrawing quaternized pyridine nitrogen and the
resulting imine was then hydrolyzed to yield crude aldehyde 12.
33
a
This material was oxidized with Ag O and converted into a
2
Reagents and conditions: (a) i. NaOH, H O, methanol; ii. H SO ,
2
2
4
methyl ester with H SO and methanol in an overall 32% yield
methanol. (b) NaOH, H O, methanol. (c) NEt , N-(3-dimethylami-
nopropyl)-N′-ethylcarbodiimide HCl, CH Cl .
2
4
2
3
from metergoline. This procedure also yielded varying amounts
of dimethyl acetal 15 (shown in Figure 4), which is presumably
2
2
formed if not all aldehyde 12 is oxidized by Ag O prior to
2
completely eliminate it, as compound 8 is a partial agonist, with
an EC50 of 16 nM and a Emax of 38%.
H SO and methanol treatment. From methyl ester 13, acetic
2
4
21
acid catalyzed amide formation furnished 14 in good yield.
Finally, heating amide 14 with ethyl isocyanate gave the desired
final product 9.
After we finished our synthesis of 6-methylcabergoline, a new
publication from the Pertz group reported that 6-methylca-
bergoline was a functional antagonist at endothelial 5-HT
2B
28
Compounds 9 and 15 showed no agonism in the IP1 5-HT2B
functional assay (n = 1) or in the intracellular calcium
mobilization 5-HT2B functional assay (n = 5), while compound
receptors in porcine pulmonary arteries. Because of the
results obtained by Pertz, we retested compound 8 in a
different human 5-HT2B functional assay in which intracellular
calcium mobilization was monitored using a FLIPR Tetra
fluorescence imaging plate reader. Compound 8 was con-
sistently a partial agonist at the human 5-HT2B receptor in this
assay, though the Emax varied from 5 to 49% (n = 5, average
Emax of 23%). We believe that the most likely explanation for
this discrepancy is interspecies differences in the 5-HT2B
receptor. While the pig and human 5-HT2B receptors have
been reported to possess a rather close 95% sequence
14 showed minimal to no agonism in these assays (Emax < 12%
in all cases). All three compounds were potent antagonists
against serotonin at the 5-HT2B receptor. These results
demonstrated that it is indeed possible to synthesize a close
analog of cabergoline in which 5-HT2B agonism has been
eliminated. Further investigation into 9 revealed that it is a full
D agonist, a potent but partial D agonist (EC 1.4 nM, Emax
4
2
50
5
0%), and a weak 5-HT2A antagonist (IC50 11.5 μM).
2
9
When the screening results for all the products synthesized
homology, there have been previous reports of compounds
having significantly different activities at receptors having
similar levels of interspecies homology, including at least two
are taken as a whole, it is possible to make two tentative
conclusions about the SAR of these novel cabergoline analogs.
First, indole-methylation and replacement of the 6-allyl with 6-
methyl both reduce the degree of functional agonism at the 5-
HT2B receptor. Second, while several of the compounds that
were made had very different substitutions at the 8-position of
the ergot alkaloid, the 5-HT2B binding activity varied
remarkably little among these compounds. These substitutions
also had only a small effect on 5-HT2B functional activity. These
results suggest that any future efforts to reduce 5-HT2B binding
activity should focus elsewhere on the scaffold.
30,31
prior examples with ergot alkaloids at serotonin receptors.
In an attempt to find compounds with less agonism at the
human 5-HT2B receptor, we next directed our attention to the
preparation of 9 (shown in Scheme 4), the indole-methylated
analog of 8. We based this choice of target on the example of
the ergot alkaloid methylergonovine, which is a partial agonist
at the 5-HT2B receptor, and its indole-methylated analog
methysergide, which has significantly weaker activity at the
17
receptor in both binding and functional assays. Rather than
begin the synthesis of 9 from dihydroergotamine, we chose
instead to start from metergoline, which is significantly less
expensive (1/25 the cost per mole) and already has a methyl
group on the indole in place. Metergoline was first Cbz-
deprotected with Pd/C and hydrogen in nearly quantitative
Our future plan is to test these compounds in animal models
of SSRI-induced sexual dysfunction. Sexual dysfunction is a
common side effect of SSRI administration and a leading cause
34
of patient noncompliance. Dopamine agonists, including
cabergoline, have been reported to reverse SSRI-induced sexual
Figure 4. Structure and activity of cabergoline and analogs in 5-HT2B binding (K) and functional assays (EC for agonists; IC50 and K for
i
50
B
antagonists).
2
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 4. Synthesis of 1,6-Dimethylcabergoline (9)
a
Reagents and conditions: (a) Pd/C, H , methanol. (b) CH Cl /DMF. (c) DBU. (d) Oxalic acid in H O, 0 °C to rt. (e) Ag O, THF, methanol, 10%
2
2
2
2
2
NaOH in H O. (f) H SO , methanol. (g) 3-(Dimethylamino)-1-propylamine; acetic acid, 120 °C. (h) Ethyl isocyanate, toluene, 115 °C.
2
2
4
dysfunction in some patients, 5−37 and we intend to use our
cabergoline analogs to help establish the pharmacological
profile necessary for a drug to have therapeutic efficacy against
this disorder in both men and women.
3
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ASSOCIATED CONTENT
■
*
S
Supporting Information
Experimental details of in vitro assays, synthetic procedures,
and characterization of all final compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Cabergoline treatment in men with psychogenic erectile dysfunction: a
randomized, double-blind, placebo-controlled study. Int. J. Impotence
Res. 2006, 19, 104−107.
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Corresponding Author
*
Tel: 612-625-7948. E-mail: pidosa@umn.edu.
Funding
This research was supported by a Grant Writers Workshop
Seed Grant from the College of Pharmacy at the University of
Minnesota.
2
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Notes
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The authors declare no competing financial interest.
randomized, double-blind, placebo-controlled study. Int. J. Impotence
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ACKNOWLEDGMENTS
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■
5
-HT binding and IP1 5-HT2B functional assays were
2B
conducted by CEREP (France). All other functional data
were generously provided by the National Institute of Mental
Health’s Psychoactive Drug Screening Program, Contract #
HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP
is directed by Bryan L. Roth MD, Ph.D., at the University of
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