Trans-2-(2,5-dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT2 receptor family

Article abstract of DOI:10.3762/bjoc.8.194

A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4- iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromoamphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT₂

Full text of DOI:10.3762/bjoc.8.194

trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclo-
propylamine and trans-2-(2,5-dimethoxy-4-
bromophenyl)cyclopropylamine as potent
agonists for the 5-HT2 receptor family
Adam Pigott1, Stewart Frescas1, John D. McCorvy1, Xi-Ping Huang2,
Bryan L. Roth2 and David E. Nichols*1,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1705–1709.
1Department of Medicinal Chemistry and Molecular Pharmacology,
College of Pharmacy, Purdue University, West Lafayette, IN 47907,
USA and 2National Institute of Mental Health, Psychoactive Drug
Screening Program, Department of Pharmacology, School of
Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
doi:10.3762/bjoc.8.194
Received: 14 June 2012
Accepted: 06 September 2012
Published: 08 October 2012
Email:
This article is part of the Thematic Series "Synthetic probes for the study
of biological function".
David E. Nichols* - drdave@purdue.edu
* Corresponding author
Guest Editor: J. Aube
§ Tel 765-494-1461; fax 765 494-1414
© 2012 Pigott et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cyclopropanation; diazomethane; hallucinogen; 5-HT2A agonist;
receptor probe; trans-2-phenylcyclopropylamines
Abstract
A strategy to replace the ethylamine side chain of 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a), and 2,5-dimethoxy-4-bromo-
amphetamine (DOB, 1b) with a cyclopropylamine moiety was successful in leading to compounds with high affinity at the 5-HT2
family of receptors; and the more potent stereoisomer of the cyclopropane analogues had the expected (−)-(1R,2S)-configuration.
Screening for affinity at various serotonin receptor subtypes, however, revealed that the cyclopropane congeners also had increased
affinity at several sites in addition to the 5-HT2A and 5-HT2B receptors. Therefore, at appropriate doses – although (−)-4 and (−)-5
may be useful as tools to probe 5-HT2 receptor function – one would need to be mindful that their selectivity for 5-HT2A receptors
is somewhat less than for DOI itself.
Introduction
Among the molecules that have proven very valuable to neuro- pensive and has been widely used throughout the neuroscience
scientists studying brain serotonin systems is the substituted community to study behaviors mediated by 5-HT2 family recep-
phenethylamine derivative 2,5-dimethoxy-4-iodoamphetamine tors. Indeed, as of June 12, 2012, a PubMed search of the terms
(DOI, 1a, Figure 1), a potent but nonspecific agonist ligand for DOI + 5-HT2 yielded 577 hits, spanning from 1984 to the
serotonin 5-HT2A and 5-HT2C receptors. It is relatively inex- present. Despite the fact that no significant abuse of DOI has
1705

Beilstein J. Org. Chem. 2012, 8, 1705–1709.
Figure 1: Structures of well-known serotonin 5-HT2A agonists 1a,b, 2, and 3, and compounds 4 and 5 reported in this paper.
been reported, this substance has been scheduled in a number of
countries and has been considered for scheduling by the U.S.
Drug Enforcement Administration (DEA). Classification as a
controlled substance will be a setback to the neuroscience
community because it effectively prevents experiments in any
laboratory that does not have a proper license for the use of
DOI. To illustrate this point, a related compound – bromo
congener 1b (DOB) – presently is a controlled substance and
only 52 hits for DOB + 5-HT2 were obtained from PubMed,
compared with 577 for DOI over the same period of time.
Table 1: Affinity values (Ki in nM) at human 5-HT2A and 5-HT2C recep-
tors. All values represent mean and SEM from at least three inde-
pendent experiments.
3H-ketanserin
3H-mesulergine
Compound
5-HT2A
5-HT2C
Ki in (nM)
Ki in (nM)
(±)-1a
(±)-1b
(±)-4
7.6 ± 0.9
8.9 ± 0.5
1.5 ± 0.1
1.4 ± 0.3
35 ± 6
31 ± 5
17 ± 3
(±)-5
7.5 ± 1.1
Anticipating the potential need for a substance to replace DOI
as a research tool, we sought to identify a molecule that might
have pharmacological properties which are identical, or at least
very similar to those of 1a. We had previously characterized the
cyclopropane analogue of a hallucinogenic amphetamine known
as DOM (2) and had shown that 3 (DMCPA) had high potency
both in vitro and in vivo [1-3]. We thus considered whether the
cyclopropane analogues 4 and 5 might be useful research tools.
Accordingly, this report details the synthesis of racemic trans-
1-(2,5-dimethoxy-4-iodophenyl)-2-aminocyclopropane (4) and
its bromo homolog 5, the resolution of 4 into its (−)-(1R,2S)-
enantiomer, as well as the resolution of the cyclopropane
carboxylic acid precursor and subsequent bromination to
provide both enantiomers of 5.
Table 2: Potency and percent max values for calcium release at
5-HT2A and 5-HT2C receptors. All values represent mean and SEM
from at least three independent experiments.
5-HT2A
5-HT2C
Compound
EC50
(nM)
%max
EC50
(nM)
%max
(−)-1a
(−)-1b
(−)-4
3.3 ± 0.7
5.8 ± 1.3
2.0 ± 0.3
6.3 ± 1.6
87 ± 1
75 ± 7
89 ± 4
8.7 ± 0.2
28 ± 4
50 ± 5
59 ± 7
63 ± 6
77 ± 6
21 ± 4
(−)-5
76 ± 10 32 ± 8
At the 5-HT2C receptor 1a was the most potent, with an EC50
that was about three times lower than for 1b, 4, or 5. In func-
tional assays, therefore, the cyclopropane analogues 4 and 5
compared to 1a or 1b appeared as potent and had a similar
degree of maximal stimulation at each of the respective 5-HT2
receptors.
Results and Discussion
Racemic 4 and 5 were compared in radioligand competition
assays against radiolabeled antagonists defined at the human
5-HT2A and 5-HT2C receptors and compared with racemic 1a
and 1b. The results are shown in Table 1. As can be seen, the
cyclopropane analogues 4 and 5 showed affinities for the
5-HT2A receptor 5–6-fold greater than 1a and 1b. Affinities at
the 5-HT2C receptor were about two-fold higher than for 1a and We then carried out a broader screen of 4 and 5 for affinities at
1b.
a range of other 5-HT receptor isoforms (Table 3). Their affini-
ties at other 5-HT receptors, however, were higher than for 1a.
The more potent (−)-enantiomers were then tested for func- In particular, the introduction of the cyclopropane appears to
tional potency using a calcium release assay. The EC50 values increase significantly affinities at the 5-HT1A, 5HT1B, and
and maximal effect at the 5-HT2A receptor were virtually iden- 5-HT1D receptors. In that regard, although (−)-4 and (−)-5 have
tical for 1a and 4, and for 1b and 5 (Table 2).
affinities at the 5-HT2A receptor somewhat higher than 1a, their
1706

Beilstein J. Org. Chem. 2012, 8, 1705–1709.
Table 3: Affinity values (Ki in nM) at selected serotonin receptor isoforms.
Cmpd
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT2A
5-HT2B
5-HT2C
5-HT6
5-HT7
(±)-1a
(±)-4
(−)-4
(+)-5
(−)-5
<50%a
410
<50%a
290
<50%a
535
1090
1660
1380
<50%a
890
9
3
19
17
7.4
130
9
1380
100
70
850
580
260
170
120
9
10
6
150
230
90
2.4
540
3
210
<50%a
375
<50%a
390
20
4
NA
45
220
a<50% displacement at 10−6 M.
selectivity over the 5-HT1A receptor is less than 100-fold. As N-carbobenzoxy intermediate, followed by catalytic debenzyla-
shown in Table 1, both 4 and 5 are extremely potent ligands in tion over Pd(C); but those conditions would lead to dehalogena-
vitro. Furthermore, as anticipated, it was the (−)-enantiomers tion in the present series, so we instead employed acid-
that proved to have highest affinity. We included (+)-5 in catalyzed removal of a BOC protecting group (Scheme 2).
Table 3 simply to illustrate the difference in affinity between
the two enantiomers. We assume that the final compounds have Thus, we first prepared 2-(2,5-dimethoxyphenyl)cyclo-
the (−)-(1R,2S) and (+)-(1S,2R) absolute configurations based propanecarboxylic acid methyl ester (7) from the corres-
on our earlier work establishing the absolute configuration of 3 ponding cinnamic ester 6 [5], followed by I2/AgNO3 iodination
[2], and the fact that substitutions at the 4-position of the (Scheme 1), and base hydrolysis of the resulting ester to provide
aromatic ring in chiral substituted amphetamines do not change iodo acid 10a. Hydrolysis of ester 7 followed by bromination of
the sign of optical rotation [4]. The biological data are consis- acid 9 using Br2-dioxane complex gave a good yield of bromo
tent with those configuration assignments.
acid 10b.
Chemistry
These acids were readily converted to their isocyanates using
We reasoned that a palladium-mediated cyclopropanation of the the Weinstock modification of the Curtius rearrangement [6].
corresponding cinnamic acids would provide the required Those isocyanates were heated with tert-butanol to afford the
cyclopropanecarboxylic acid (Scheme 1); which could be corresponding carbamates 11a and 11b (Scheme 2). A brief
readily converted to the amine by a Curtius type rearrangement treatment of these with 3 M HCl at 45 °C cleanly affected
(Scheme 2). In our previous synthesis [2] we had employed an N-deprotection and afforded the desired final amines 4 and 5.
Scheme 1: Synthesis of arylcyclopropane carboxylic acids from the corresponding cinnamic acids, followed by halogenation.
1707

Beilstein J. Org. Chem. 2012, 8, 1705–1709.
Scheme 2: Conversion of arylcyclopropane carboxylic acids 10a,b to the amines 4 and 5, and chemical resolution of 4 into its enantiomers.
The stereochemistry of the more potent enantiomer of DOI is solvents also led to nearly complete decomposition, although
(−)-(R) [7], and of 3 is (−)-(1R,2S) [2]. We therefore undertook salts of bromo compound 5 appeared somewhat more stable.
the resolution of the enantiomers of DOI by fractional crystal-
lization of the diastereomeric salts prepared with di-O,O- We then followed a more efficient divergent approach to obtain
benzoyltartaric acid. Unfortunately, we discovered that heating the enantiomers of 5 that employed resolution of the cyclo-
solutions of the dibenzoyltartrate salt of 4 in EtOH or iPrOH led propane carboxylic acid, followed by bromination, and then
to nearly complete decomposition, presumably through a cyclo- conversion to the cyclopropylamine (Scheme 3). We are aware
propane ring-opening pathway. The apparent need to recrystal- that the use of chiral auxiliaries in the cyclopropanation step
lize the O,O-dibenzoyltartrate salts from a nonprotic solvent led could directly afford the chiral cyclopropane acids [8], but time
us to employ warm acetone, which proved satisfactory. The and resources did not allow us to pursue that approach.
resolution went well, achieving constant optical rotation after
only three crystallizations. The salt was converted to the free Conclusion
base, which was dissolved in dry Et2O, followed by addition of In conclusion, our strategy to replace the ethylamine side chain
the stoichiometric amount of ethereal HCl. The salt precipitated of 1a (or 1b) with a cyclopropylamine moiety was successful in
out of solution and could be used directly for pharmacological leading to compounds with high affinity at the 5-HT2 family of
experiments. Attempts to recrystallize the HCl salt from protic receptors; and the more potent stereoisomer of the cyclo-
Scheme 3: Chemical resolution of arylcyclopropane carboxylic acid 9 followed by bromination.
1708

Beilstein J. Org. Chem. 2012, 8, 1705–1709.
9. Vangveravong, S.; Kanthasamy, A.; Lucaites, V. L.; Nelson, D. L.;
Nichols, D. E. J. Med. Chem. 1998, 41, 4995–5001.
doi:10.1021/jm980318q
propane analogues had the expected (−)-1R,2S-configuration.
However, at appropriate doses, although (−)-4 and (−)-5 may be
useful as tools to probe 5-HT2 receptor function, one would also
need to be mindful that their selectivity for 5-HT2A over
5-HT1A is only about 70-fold.
License and Terms
The most efficient approach appears to be the synthesis of the
chiral cyclopropane carboxylic acids, followed by derivatiza-
tion at the 4-position. This approach would be most appealing if
a chiral auxiliary was used in the cyclopropanation step [8]. We
also note that compound 4 was less stable than 5 under recrys-
tallization conditions, an instability we did not observe during
our earlier work with 3. We have observed even greater insta-
bility in 2-(indol-3-yl)cyclopropylamines [8,9], suggesting that
electron “excessive” π-systems, or the ability to “donate” elec-
trons through resonance (i.e. Br and I), leads to cyclopropane
ring instability in 2-arylcyclopropylamines.
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.194
Supporting Information
Supporting Information File 1
Experimental details for all new compounds as well as the
pharmacological methods used to measure receptor affinity
and functional activity.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-194-S1.pdf]
Acknowledgments
This research was supported by the Robert C. and Charlotte P.
Anderson endowment.
References
1. Nichols, D. E.; Pfister, W. R.; Yim, G. K. W. Life Sci. 1978, 22,
2165–2170. doi:10.1016/0024-3205(78)90567-2
2. Nichols, D. E.; Woodard, R.; Hathaway, B. A.; Lowy, M. T.;
Yim, G. K. W. J. Med. Chem. 1979, 22, 458–460.
doi:10.1021/jm00190a021
3. Johnson, M. P.; Mathis, C. A.; Shulgin, A. T.; Hoffman, A. J.;
Nichols, D. E. Pharmacol. Biochem. Behav. 1990, 35, 211–217.
doi:10.1016/0091-3057(90)90228-A
4. Nichols, D. E.; Barfknecht, C. F.; Rusterholz, D. B.; Benington, F.;
Morin, R. D. J. Med. Chem. 1973, 16, 480–483.
doi:10.1021/jm00263a013
5. Peterson, J. R.; Russell, M. E.; Surjasasmita, I. B. J. Chem. Eng. Data
1988, 33, 534–537. doi:10.1021/je00054a042
6. Weinstock, J. J. Org. Chem. 1961, 26, 3511. doi:10.1021/jo01067a604
7. Johnson, M. P.; Hoffman, A. J.; Nichols, D. E.; Mathis, C. A.
Neuropharmacology 1987, 26, 1803–1806.
doi:10.1016/0028-3908(87)90138-9
8. Vangveravong, S.; Nichols, D. E. J. Org. Chem. 1995, 60, 3409–3413.
doi:10.1021/jo00116a028
1709