Research Article

pubs.acs.org/chemneuro

Synthesis and Structure−Activity Relationships of N‑Benzyl

Phenethylamines as 5‑HT2A/2C Agonists
Martin Hansen, Karina Phonekeo, James S. Paine, Sebastian Leth-Petersen, Mikael Begtrup,
Hans Braü ner-Osborne, and Jesper L. Kristensen*
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen,
Universitetsparken 2, 2100 København Ø, Denmark
*
S Supporting Information

ABSTRACT: N-Benzyl substitution of 5-HT2A receptor agonists

of the phenethylamine structural class of psychedelics (such as 4-
bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B)
confer a significant increase in binding affinity as well as
functional activity of the receptor. We have prepared a series of
48 compounds with structural variations in both the phenethyl-
amine and N-benzyl part of the molecule to determine the effects
on receptor binding affinity and functional activity at 5-HT2A and
5-HT2C receptors. The compounds generally had high affinity for
the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting
subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the
most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor
in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the
functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.
KEYWORDS: Serotonin, 5-HT2A receptor agonist, N-benzyl phenethylamines, selectivity

S erotonin (5-HT) receptors are widely distributed in both

the CNS and the peripheral nervous system and are
involved in the regulation of a plethora of physiological
148) have been investigated as a prophylactic treatment of
cluster headaches, and inverse agonists such as risperidone and
clozapine are well-known atypical antipsychotics.17,18
responses such as cognition, memory processing, mood, 5-HT2A agonists have traditionally been divided into three
circadian behavior, and appetite.1 The 5-HT2A receptor appears structural groups: Ergolines, tryptamines, and phenethyl-
to play a key role in a number of disease states such as amines.19 The ergoline group is named after the ergot fungus
addiction,2 schizophrenia,3 obsessive compulsive disorder,4,5 which was the initial source of ergot alkaloids, but ergolines are
depression,6,7 pain,8 inflammation,9 migraine,10 and cluster also known to occur naturally in several other species of plant
headaches,11 and in the manifestation of mystical/religious-type and fungi.20 The ergolines comprise a varied group of
experiences as well as in altered states of consciousness.3,12−15 compounds with a rich pharmacology and bind to many
Agonist activation of 5-HT2A receptors in the cortex is believed types of monoamine receptors both serotonergic and non-
to be responsible for the remarkable psychopharmacological serotonergic. Not all ergolines are 5-HT2A agonists and several
effects exerted by hallucinogens such as lysergic acid are used clinically in the treatment of migraine,21 Parkinson’s
diethylamide (LSD) and psilocybin; see Figure 1.16 Neutral disease and in obstetrics.22,23
antagonists such as 2-bromolysergic acid diethylamide (BOL- Tryptamines are slightly more selective compounds but
usually have strong affinity for several 5-HT receptors.
Serotonin itself is an agonist at all 5-HT receptors, whereas
the classical hallucinogens psilocybin and N,N-dimethyltrypt-
amine (DMT) activate 5-HT1A receptors as well as the 5-HT2
subtypes.
Phenethylamines are generally selective for the 5-HT2
receptor subtypes but lack selectivity between the individual
subtypes.24 The optimal substitution pattern and molecular
configuration for simple phenethylamines have been refined

Figure 1. Representative members of the three structural groups of 5-

Received: December 5, 2013
HT2A agonists. LSD (an ergoline), psilocybin (a tryptamine), and
mescaline (a phenethylamine). Revised: January 7, 2014

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ACS Chemical Neuroscience Research Article

and improved during the past 40 years and have resulted in Scheme 1. Synthesis of N-Benzyl Phenethylaminesa
some very potent agonists.25,26
Initially, N-substituted phenethylamines were thought to be
inferior compared to the parent phenethylamines because early
studies involving N-alkylation with simple substituents (e.g.,
methyl, ethyl, propyl) produced compounds with significantly
diminished activity.27,28 Therefore, it was surprising when it was
discovered that N-benzyl and specifically N-(2-methoxy)benzyl
substitution dramatically improved both binding affinity and
functional activity and in vivo 5-HT2A activation of simple
phenethylamines such as 2C-I (4-iodo-2,5-dimethoxyphene-
thylamine).29,30 This discovery was later expanded upon to a
include conformationally restricted N-benzylphenethylamines Reaction conditions: (i) aldehyde, EtOH, rt; (ii) NaBH4, EtOH, rt.
which resulted in the first truly selective 5-HT2A agonist.31
As part of our efforts to develop an agonist PET-tracer for
the 5-HT2A receptor, we have examined a number of different
■ IN VITRO PHARMACOLOGY
All compounds were assessed in a radioligand competition
N-benzylphenethylamines for their ability to bind to and binding assay for affinity at human 5-HT2A receptors and rat 5-
activate 5-HT2A receptors in the search for a 5-HT2A selective HT2C receptors using displacement of antagonist radioligands
agonist.32 Agonists are of special interest in PET studies [3H]Ketanserin and [3H]Mesulergine via the NIMH Psycho-
because agonist PET-ligands only label receptors in the active, active Drug Screening Program (PDSP). The results are
high-affinity state which provides more functionally relevant summarized in Figure 2. In Figure 3, the 5-HT2A/2C selectivities
imaging. Furthermore, agonist PET-ligands are potentially based on the data in Figure 2 are presented.
more sensitive to changes in synaptic serotonin levels due to Functional assays were performed on all compounds to
the higher affinity of 5-HT for agonist versus antagonist labeled determine the ability of the ligands to activate downstream
receptors. Several ligands from the study have been investigated cellular signaling pathways. The compounds were examined for
their efficacy at stimulating phospholipase C mediated
as PET-ligands, and 5a (under the alias Cimbi-36) is currently
production of inositol phosphates (IP1−3) at both human 5-
being evaluated in humans.33 Herein we wish to report the full
HT2A and 5-HT2C receptors. The results are summarized in
details on the medicinal chemistry development of these Figure 4; see the Supporting Information for full details.

■
ligands. We wanted to study the impact of the 4-substituent on
N-benzylphenethylamines with a small set of N-benzyl RESULTS AND DISCUSSION
substituents and determine the effects on both binding affinity The results from the binding affinity measurements showed
and functional activity at the 5-HT2A receptor as well as the 5- that the majority of the compounds bind to both 5-HT2A and 5-
HT2C receptor. Extensive structure−activity relationship (SAR) HT2C receptors in the low nanomolar range with several
studies have previously been performed on the 4-position of compounds having subnanomolar affinities (pKi above 9) at the
psychedelic phenethylamines and amphetamines.27,34 These 5-HT2A receptor. Previously, a smaller subset of compounds
studies revealed that 4-substituents containing hydrogen bond were subjected to a broader screen which showed the N-benzyl
donors such as −COOH, −OH, and −NH2 decrease affinity by phenethylamines are highly selective for the 5-HT2 receptor
several orders of magnitude while nonpolar substituents such as subtypes over a wide selection of other neuroreceptors.32
halogens and alkyl groups increased affinity. Thus, there seems Ligands substituted with F, CN, or Me at the 4-position of the
to be a clear correlation between the lipophilic nature of the phenethylamine core (4a−d, 6a−d, and 7a−d) have slightly
substituent in the 4-position and binding affinity; however, only lower affinities which is in accordance with affinity data
halogens and short alkyl chains (1−4 carbons) are agonists published previously on simple/primary phenethylamines and
while longer alkyl chains, aryl and benzyl groups are antagonists amphetamines.35 In general, the ligands with a N-(2-
fluorobenzyl) substituent (1c−12c) have lower affinities than
at the 5-HT2A receptor.
the other N-benzyl substituents which could be due to a
Herein we report our efforts to investigate the SAR of this diminished hydrogen bond acceptor capability.
compound family via a systematic variation of substituents on While all compounds were generally 5-HT2A-selective in the
the phenethylamine and benzyl rings. Twelve phenethylamines binding assays, the selectivity varied with the nature of both the
were paired with 4 benzaldehydes to give a set of 48 N-benzyl 4-substituents and the N-benzyl substituents. 2,3-Methylene-
phenethylamines that subsequently were evaluated on the 5- dioxy substitution on the N-benzyl part results in a general
HT2A and 5-HT2C receptors in binding and functional assays. increase in the 5-HT2A-selective binding with most 4-

■
substituents; see Figure 3. The influence of the other N-benzyl
CHEMISTRY substituents on 5-HT2A/2C-selectivity was too erratic to show
any general trends. The same applies to the 4-substituents
The targeted 48 compounds were all synthesized by indirect which do not display any general trends. In Figure 5, 5b, 5d, 6b,
reductive amination of the respective phenethylamines and and 6d are shown for comparison. Compound 5b is a very
benzaldehydes as shown in Scheme 1. The N-benzylphenethyl- potent agonist with 85-fold selectivity in the functional assays,
amines were precipitated as their hydrochloride salts in 46− but low selectivity (3-fold) in the binding assay. In 5d, the
94% isolated yields. The syntheses of the parent 12 methylenedioxy moiety in the N-benzyl group increases the
phenethylamines have been described previously; see the selectivity to a factor of 226 and 18, respectively, while
Supporting Information for details. maintaining potency. Exchanging the CF3-group for a CN-
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ACS Chemical Neuroscience Research Article

Figure 2. Binding affinities (pKi) of N-benzylphenethylamines at the 5-HT2A and 5-HT2C receptor. See the Supporting Information for tables with all
data.

Figure 3. Graph showing the 5-HT2A/5-HT2C selectivities based on binding affinities.

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Figure 4. Functional characterization of N-benzylphenethylamines at human 5-HT2A and 5-HT2C receptors. Top half shows pEC50, whereas bottom
half represents intrinsic activity.

affinity and selectivity for 5-HT 2A . In Figure 6, the

concentration−response curves for 6b and 6d on 5-HT2A and
5-HT2C are compared with DOI. As can be seen in Figure 3, the
combination of the 4-CN and N-(2-hydroxybenzyl) substitu-
ents in 6b gives the most selective compound in the series with
respect to binding affinities. In simple amphetamines with the
same substitution pattern, the 4-CN substitution results in a
moderate (20-fold) selectivity toward 5-HT2A, and it appears
that this property is augmented by the 2′-hydroxybenzyl
substituent but not by the other N-benzyl groups examined in
this study. Attempts to rationalize the structure−activity
relationships via docking of the ligand set in previously
reported 5-HT2A/2C homology-models were unsuccessful.35
In the functional assay, the N-(2-hydroxybenzyl) substituted
compounds generally showed the highest activity at the 5-HT2A
receptor with moderate to good selectivity. With very few
exceptions, the intrinsic activity was above 70% for all
compounds on both 5-HT2A and 5-HT2C. N-(2-Methoxyben-
zyl) compounds (1−12a) were less active and also less selective
Figure 5. Structure and in vitro pharmacological profile of 5b, 5d, 6b,
5-HT2A agonists. From the N-(2-hydroxybenzyl) compounds,
and 6d. 1b emerged as the most functionally potent of all ligands tested
with an EC50 of 0.074 nM with more than 400-fold selectivity
group in these two compounds gives two very different results: for the 5-HT2A receptor. The N-(2,3-methylenedioxybenzyl)
6b retains the high affinity for 5-HT2A, while affinity for 5-HT2C substituted compounds (1d−12d) were generally less potent.
diminishes, giving a 100-fold selective compound, whereas in The N-(2-fluorobenzyl) compounds (1c−12c) were inferior in
6d the same CF3 to CN substitution leads to an erosion of both terms of affinity, efficacy, and selectivity compared to the other
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ACS Chemical Neuroscience Research Article

compounds emerged. Several compounds displayed affinities

and potencies in the picomolar range with varying levels of
selectivity. Although the structure activity relations of the 48
ligands were erratic, the effect of the cyano substituent in the 4-
position and the general trend of the N-(2,3-methylenediox-
ybenzyl) substituted phenethylamines on the selectivity is an
interesting new observation. The most selective compound
(when taking both binding and functional data into account)
was 6b being 100- and 90-fold selective; see Figure 8. In 2013,

Figure 8. Comparison between 5d and 5-HT2A selective agonist

published by Juncosa et al. in 2013.

Juncosa et al.31 published a conformationally restrained N-

benzyl phenethylamine with more than 100-fold selectivity for
the 5-HT2A receptor; see Figure 8. We are currently pursuing
Figure 6. Concentration−response curves of the agonists DOI, 6b and ligands where these structural motifs are merged in the search
6d at 5-HT 2A (A) and 5-HT2C (B) receptors, respectively. for even more selective 5-HT2A agonists.
Concentration−response curves were generated from stimulation of
inositol phosphate formation in tsA cells transiently expressing either
5-HT2A (A) or 5-HT2C (B) receptors. The formation of inositol
phosphate was determined as described in Methods and calculated as
■ METHODS
Synthesis of Secondary Amines. Et3N (1.0 equiv) was added to
a suspension of the phenethylamine hydrochloride (1.0 mmol) and
percent response compared to a full 5-HT response. Data shown are aldehyde (1.1 equiv) in EtOH (10 mL), and the reaction was stirred
mean ± SD of a single representative experiment performed in until formation of the imine was complete according to TLC or GC
triplicate. Two additional experiments gave similar results. (30 min to 3 h). NaBH4 (2.0 mmol) was added, and the reaction was
stirred for another 30 min. The reaction mixture was concentrated
three series, mirroring the results from the binding assays, but under reduced pressure and partitioned between CH2Cl2/H2O (30
comparable to the parent phenethylamines. mL, 1:1). The organic layer was isolated, and the aqueous layer was
extracted with CH2Cl2 (2 × 15 mL). The combined organic extracts
In simple phenethylamines, the functional activity drops as were dried (Na2SO4), filtered, and evaporated under reduced pressure.
the size of the 4-substituent is increased. This is mirrored in our The residue was purified by flash chromatography (CH2Cl2/MeOH/
result: Starting from 4-methyl (7b), there is a drop in activity NH3 98:2:0.04). The purified free base was dissolved in EtOH (2 mL),
going from ethyl (8b) to propyl (9b) with the N-(2- there was added ethanolic HCl (1M, 2 mL), and the solution was
hydroxybenzyl) substituent. In the N-(2,3-methylendioxyben- diluted with Et2O until crystals formed. The crystals were collected by
zyl) series, the trend is similar; in the 4-thioalkyl series, 10d− filtration and dried under reduced pressure.
11d−12, where 11d is the most potent of the three; see Figure Functional Pharmacology. Cell culturing, transfection, and
7. Thus, it appears that the substituent on the N-benzyl inositol phosphate turnover assay were adopted from a previously
somehow influences the interaction of the 4-substituent as well. published procedure.36
Cell Culture and Transfections. tsA201 cells (a transformed
In conclusion, we have investigated the structure activity HEK293 cell line) were cultured in GlutaMAX-I Dulbecco’s modified
relationship of 48 closely related N-benzyl phenethylamines as Eagle’s medium (DMEM) supplemented with 10% dialyzed fetal
5-HT2A/2C agonists. From that study, several interesting bovine serum, penicillin (100 U mL−1), and streptomycin (100 mg
mL−1) at 37 °C in a humidified atmosphere of 95% air and 5% CO2.
Constructs encoding human 5-HT2A and 5-HT2C in pcDNA3.1 were
obtained from the Missouri S&T cDNA Resource Center (www.cdna.
org) and transiently transfected into cells using PolyFect according to
the manufacturer’s protocol (Qiagen, West Sussex, U.K.).
Inositol Phosphate (IP) Turnover Assay. The day after
transfection, tsA201 cells were split into poly-D-lysine-coated 96-well
tissue culture plates in inositol-free DMEM supplemented with 10%
dialyzed fetal bovine serum, penicillin (100 U mL−1), streptomycin
(100 mg mL−1), and 4 μCi mL−1 myo-[2-3H]inositol (GE Healthcare,
Buckinghamshire, U.K.). Two days after transfection, cells were
washed with assay buffer 1 (Hanks’ balanced saline solution (HBSS)
containing 20 mM HEPES, 1 mM CaCl2, 1 mM MgCl2, and 1 mg
Figure 7. Structure and in vitro pharmacological profile of 7b−9b and mL−1 BSA, pH 7.4) and preincubated in 100 μL assay buffer 1 for 4 h
10d−12d. at 37 °C, where the buffer was replaced after 2 h. The cells were then

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ACS Chemical Neuroscience Research Article

washed and subsequently incubated in 50 μL of assay buffer 2 (HBSS (4) Adams, K. H., Hansen, E. S., Pinborg, L. H., Hasselbalch, S. G.,
containing 1 mM CaCl2, 1 mM MgCl2, and 20 mM LiCl) for 30 min Svarer, C., Holm, S., Bolwig, T. G., and Knudsen, G. M. (2005)
at 37 °C. Following this incubation, the cells were stimulated with 50 Patients with obsessive-compulsive disorder have increased 5-HT2A
μL of the indicated agonists in assay buffer 2 for 30 min at 37 °C. receptor binding in the caudate nuclei. Int. J. Neuropsychopharmacol. 8
The reactions were stopped by exchanging the buffer with 50 μL (3), 391−401.
ice-cold 10 mM formic acid and incubating the cells at 4 °C for at least (5) Moreno, F. A., Wiegand, C. B., Taitano, E. K., and Delgado, P. L.
30 min. Yttrium silicate scintillation proximity assay beads (GE (2006) Safety, tolerability and efficacy of psilocybin in 9 patients with
Healthcare, Buckinghamshire, U.K.) were used for measuring obsessive compulsive-compulsive disorder. J. Clin. Psychiatry 67 (11),
radioactivity from generated [3H]-IP essentially as previously 1735−1740.
described.37 In brief, 20 μL of the formic acid cell extracts were (6) Celada, P., Puig, M. V., Amargós-Bosch, M., Adell, A., and
transferred to white 96-well plates, and 1 mg of yttrium silicate Artigas, F. (2004) The therapeutic role of 5-HT1A and 5-HT2A
scintillation proximity assay beads suspended in 80 μL water added to receptors in depression. J. Psychiatry Neurosci. 29 (4), 252−265.
each well. The plates were sealed, shaken vigorously for 1 h, and (7) Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M.,
centrifuged at 1500 rpm for 5 min. The radioactivity was quantified in
Reed, L. J., Colasanti, A., Tyacke, R. J., Leech, R., Malizia, A. L.,
a Wallac Microbeta scintillation counter, and responses read as counts
Murphy, K., Hobden, P., Evans, J., Feilding, A., Wise, R. G., and Nutt,
per minute (CPM). All experiments were performed in triplicate and
repeated in at least three independent experiments. D. J. (2012) Neural correlates of the psychedelic state as determined

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by fMRI studies with psilocybin. Proc. Natl. Acad. Sci. U.S.A. 109 (6),
2138−2143.
ASSOCIATED CONTENT (8) Okamoto, K., Imbe, H., Kimura, A., Donishi, T., Tamai, Y., and
*
S Supporting Information Senba, E. (2007) Activation of central 5HT2A receptors reduces the
NMR-data, including copies of 1H and 13C NMR spectra and craniofacial nociception of rats. Neuroscience 147 (4), 1090−1102.
full details on the pharmacological characterization. This (9) Nau, F., Jr., Yu, B., Martin, D., and Nichols, C. D. (2013)
material is available free of charge via the Internet at http:// Serotonin 5-HT2A Receptor Activation Blocks TNF-a Mediated
Inflammation In Vivo. PLoS One 8 (10), e75426.
pubs.acs.org.

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(10) Hamel, E. (2007) Serotonin and migraine: biology and clinical
implications. Cephalalgia 27 (11), 1293−1300.
AUTHOR INFORMATION (11) Sewell, R. A., Halpern, J. H., and Pope, H. G., Jr. (2006)
Corresponding Author Response of cluster headache to psilocybin and LSD. Neurology 66
*Phone: +45 3533 6487. E-mail: jesper.kristensen@sund.ku.dk. (12), 1920−1922.
(12) Griffiths, R. R., Richards, W. A., McCann, U., and Jesse, R.
Author Contributions (2006) Psilocybin can occasion mystical-type experiences having
J.K., M.H., M.B., and H.B.O. conceived the experiments. M.H. substantial and sustained personal meaning and spiritual significance.
and J.S.P. synthesized the compounds. M.H. and S.L.P. Psychopharmacology 187 (3), 268−283.
characterized the compounds. K.P. and H.B.O. performed the (13) Griffiths, R., Richards, W., Johnson, M., McCann, U., and Jesse,
functional assays. M.H., S.L.P., and J.L.K. prepared the R. (2008) Mystical-type experiences occasioned by psilocybin mediate
manuscript. the attribution of personal meaning and spiritual significance 14
months later. J. Psychopharmacol. 22 (6), 621−632.
Funding
(14) Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D.,
The Lundbeck foundation, the Danish Ministry of Science, McCann, U., and Jesse, R. (2011) Psilocybin occasioned mystical-type
Innovation, and Higher Education and the The A. P. Møller experiences: immediate and persisting dose-related effects. Psycho-
Foundation for the Advancement of Medical Sciences are pharmacology 218, 649−665.
gratefully acknowledged for financial support. (15) Vollenweider, F. X., and Geyer, M. A. (2001) A systems model
Notes of altered consciousness: integrating natural and drug-induced
The authors declare no competing financial interest. psychoses. Brain Res. Bull. 56 (5), 495−507.

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(16) Nichols, D. E. (2004) Hallucinogens. Pharmacol. Ther. 2, 131−
81.
ACKNOWLEDGMENTS (17) Karst, M., Halpern, J. H., Bernateck, M., and Passie, T. (2010)
Radioligand competition binding assay for affinity at human 5- The non-hallucinogen 2-bromo-lysergic acid diethylamide as pre-
HT2A receptors and rat 5-HT2C receptors using displacement of ventative treatment for cluster headache: an open, non-randomized
antagonist radioligands [3H]Ketanserin and [3H]Mesulergine case series. Cephalalgia 30 (9), 1140−1144.
was generously provided by the National Institute of Mental (18) Weiner, D. M., Burstein, E. S., Nash, N., Croston, G. E., Currier,
Health’s Psychoactive Drug Screening Program, Contract # E. A., Vanover, K. E., Harvey, S. C., Donohue, E., Hansen, H. C.,
HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP Andersson, C. M., Spalding, T. A., Gibson, D. F., Krebs-Thomson, K.,
Powell, S. B., Geyer, M. A., Hacksell, U., and Brann, M. R. (2001) 5-
is Directed by Bryan L. Roth MD, PhD at the University of
hydroxytryptamine 2A receptor inverse agonists as antipsychotics. J.
North Carolina at Chapel Hill and Project Officer Jamie Driscol Pharmacol. Exp. Ther. 299 (1), 268−276.
at NIMH, Bethesda MD.

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(19) Nichols, D. E. (2012) Structure−activity relationships of
serotonin 5-HT 2A agonists. WIREs Membr. Transp. Signaling 1,
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