Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists

Article abstract of DOI:10.1021/cn400216u

N-Benzyl substitution of 5-HT_2A 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 phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT_2A and 5-HT_2C receptors. The compounds generally had high affinity for the 5-HT_2A 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-HT_2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT_2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT_2A receptor.

Full text of DOI:10.1021/cn400216u

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 Brauner-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
erotonin (5-HT) receptors are widely distributed in both
the CNS and the peripheral nervous system and are
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
S
involved in the regulation of a plethora of physiological
responses such as cognition, memory processing, mood,
circadian behavior, and appetite.1 The 5-HT2A receptor appears
to play a key role in a number of disease states such as
addiction,2 schizophrenia,3 obsessive compulsive disorder,4,5
depression,6,7 pain,8 inflammation,9 migraine,10 and cluster
headaches,11 and in the manifestation of mystical/religious-type
experiences as well as in altered states of consciousness.3,12−15
Agonist activation of 5-HT2A receptors in the cortex is believed
to be responsible for the remarkable psychopharmacological
effects exerted by hallucinogens such as lysergic acid
diethylamide (LSD) and psilocybin; see Figure 1.16 Neutral
antagonists such as 2-bromolysergic acid diethylamide (BOL-
5-HT2A agonists have traditionally been divided into three
structural groups: Ergolines, tryptamines, and phenethyl-
amines.19 The ergoline group is named after the ergot fungus
which was the initial source of ergot alkaloids, but ergolines are
also known to occur naturally in several other species of plant
and fungi.20 The ergolines comprise a varied group of
compounds with a rich pharmacology and bind to many
types of monoamine receptors both serotonergic and non-
serotonergic. Not all ergolines are 5-HT2A agonists and several
are used clinically in the treatment of migraine,21 Parkinson’s
disease and in obstetrics.22,23
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-
HT2A agonists. LSD (an ergoline), psilocybin (a tryptamine), and
mescaline (a phenethylamine).
Received: December 5, 2013
Revised: January 7, 2014
© XXXX American Chemical Society
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a
and improved during the past 40 years and have resulted in
some very potent agonists.25,26
Scheme 1. Synthesis of N-Benzyl Phenethylamines
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
include conformationally restricted N-benzylphenethylamines
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
N-benzylphenethylamines for their ability to bind to and
activate 5-HT2A receptors in the search for a 5-HT2A selective
agonist.32 Agonists are of special interest in PET studies
because agonist PET-ligands only label receptors in the active,
high-affinity state which provides more functionally relevant
imaging. Furthermore, agonist PET-ligands are potentially
more sensitive to changes in synaptic serotonin levels due to
the higher affinity of 5-HT for agonist versus antagonist labeled
receptors. Several ligands from the study have been investigated
as PET-ligands, and 5a (under the alias Cimbi-36) is currently
being evaluated in humans.33 Herein we wish to report the full
details on the medicinal chemistry development of these
ligands. We wanted to study the impact of the 4-substituent on
N-benzylphenethylamines with a small set of N-benzyl
substituents and determine the effects on both binding affinity
and functional activity at the 5-HT2A receptor as well as the 5-
HT2C receptor. Extensive structure−activity relationship (SAR)
studies have previously been performed on the 4-position of
psychedelic phenethylamines and amphetamines.27,34 These
studies revealed that 4-substituents containing hydrogen bond
donors such as −COOH, −OH, and −NH2 decrease affinity by
several orders of magnitude while nonpolar substituents such as
halogens and alkyl groups increased affinity. Thus, there seems
to be a clear correlation between the lipophilic nature of the
substituent in the 4-position and binding affinity; however, only
halogens and short alkyl chains (1−4 carbons) are agonists
while longer alkyl chains, aryl and benzyl groups are antagonists
at the 5-HT2A receptor.
a
Reaction conditions: (i) aldehyde, EtOH, rt; (ii) NaBH4, EtOH, rt.
IN VITRO PHARMACOLOGY
■
All compounds were assessed in a radioligand competition
binding assay for affinity at human 5-HT2A receptors and rat 5-
HT2C receptors using displacement of antagonist radioligands
[3H]Ketanserin and [3H]Mesulergine via the NIMH Psycho-
active Drug Screening Program (PDSP). The results are
summarized in Figure 2. In Figure 3, the 5-HT2A/2C selectivities
based on the data in Figure 2 are presented.
Functional assays were performed on all compounds to
determine the ability of the ligands to activate downstream
cellular signaling pathways. The compounds were examined for
their efficacy at stimulating phospholipase C mediated
production of inositol phosphates (IP1−3) at both human 5-
HT2A and 5-HT2C receptors. The results are summarized in
Figure 4; see the Supporting Information for full details.
RESULTS AND DISCUSSION
■
The results from the binding affinity measurements showed
that the majority of the compounds bind to both 5-HT2A and 5-
HT2C receptors in the low nanomolar range with several
compounds having subnanomolar affinities (pKi above 9) at the
5-HT2A receptor. Previously, a smaller subset of compounds
were subjected to a broader screen which showed the N-benzyl
phenethylamines are highly selective for the 5-HT2 receptor
subtypes over a wide selection of other neuroreceptors.32
Ligands substituted with F, CN, or Me at the 4-position of the
phenethylamine core (4a−d, 6a−d, and 7a−d) have slightly
lower affinities which is in accordance with affinity data
published previously on simple/primary phenethylamines and
amphetamines.35 In general, the ligands with a N-(2-
fluorobenzyl) substituent (1c−12c) have lower affinities than
the other N-benzyl substituents which could be due to a
diminished hydrogen bond acceptor capability.
Herein we report our efforts to investigate the SAR of this
compound family via a systematic variation of substituents on
the phenethylamine and benzyl rings. Twelve phenethylamines
were paired with 4 benzaldehydes to give a set of 48 N-benzyl
phenethylamines that subsequently were evaluated on the 5-
HT2A and 5-HT2C receptors in binding and functional assays.
While all compounds were generally 5-HT2A-selective in the
binding assays, the selectivity varied with the nature of both the
4-substituents and the N-benzyl substituents. 2,3-Methylene-
dioxy substitution on the N-benzyl part results in a general
increase in the 5-HT2A-selective binding with most 4-
substituents; see Figure 3. The influence of the other N-benzyl
substituents on 5-HT2A/2C-selectivity was too erratic to show
any general trends. The same applies to the 4-substituents
which do not display any general trends. In Figure 5, 5b, 5d, 6b,
and 6d are shown for comparison. Compound 5b is a very
potent agonist with 85-fold selectivity in the functional assays,
but low selectivity (3-fold) in the binding assay. In 5d, the
methylenedioxy moiety in the N-benzyl group increases the
selectivity to a factor of 226 and 18, respectively, while
maintaining potency. Exchanging the CF3-group for a CN-
CHEMISTRY
■
The targeted 48 compounds were all synthesized by indirect
reductive amination of the respective phenethylamines and
benzaldehydes as shown in Scheme 1. The N-benzylphenethyl-
amines were precipitated as their hydrochloride salts in 46−
94% isolated yields. The syntheses of the parent 12
phenethylamines have been described previously; see the
Supporting Information for details.
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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-HT2A. 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
5-HT2A agonists. From the N-(2-hydroxybenzyl) compounds,
Figure 5. Structure and in vitro pharmacological profile of 5b, 5d, 6b,
1b emerged as the most functionally potent of all ligands tested
and 6d.
with an EC50 of 0.074 nM with more than 400-fold selectivity
for the 5-HT2A receptor. The N-(2,3-methylenedioxybenzyl)
substituted compounds (1d−12d) were generally less potent.
The N-(2-fluorobenzyl) compounds (1c−12c) were inferior in
terms of affinity, efficacy, and selectivity compared to the other
group in these two compounds gives two very different results:
6b retains the high affinity for 5-HT2A, while affinity for 5-HT2C
diminishes, giving a 100-fold selective compound, whereas in
6d the same CF3 to CN substitution leads to an erosion of both
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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
ligands where these structural motifs are merged in the search
for even more selective 5-HT2A agonists.
Figure 6. Concentration−response curves of the agonists DOI, 6b and
6d at 5-HT2A (A) and 5-HT2C (B) receptors, respectively.
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
percent response compared to a full 5-HT response. Data shown are
METHODS
■
Synthesis of Secondary Amines. Et3N (1.0 equiv) was added to
a suspension of the phenethylamine hydrochloride (1.0 mmol) and
aldehyde (1.1 equiv) in EtOH (10 mL), and the reaction was stirred
until formation of the imine was complete according to TLC or GC
(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
under reduced pressure and partitioned between CH2Cl2/H2O (30
mL, 1:1). The organic layer was isolated, and the aqueous layer was
extracted with CH2Cl2 (2 × 15 mL). The combined organic extracts
were dried (Na2SO4), filtered, and evaporated under reduced pressure.
The residue was purified by flash chromatography (CH2Cl2/MeOH/
NH3 98:2:0.04). The purified free base was dissolved in EtOH (2 mL),
there was added ethanolic HCl (1M, 2 mL), and the solution was
diluted with Et2O until crystals formed. The crystals were collected by
filtration and dried under reduced pressure.
mean
SD of a single representative experiment performed in
triplicate. Two additional experiments gave similar results.
three series, mirroring the results from the binding assays, but
comparable to the parent phenethylamines.
In simple phenethylamines, the functional activity drops as
the size of the 4-substituent is increased. This is mirrored in our
result: Starting from 4-methyl (7b), there is a drop in activity
going from ethyl (8b) to propyl (9b) with the N-(2-
hydroxybenzyl) substituent. In the N-(2,3-methylendioxyben-
zyl) series, the trend is similar; in the 4-thioalkyl series, 10d−
11d−12, where 11d is the most potent of the three; see Figure
7. Thus, it appears that the substituent on the N-benzyl
somehow influences the interaction of the 4-substituent as well.
In conclusion, we have investigated the structure activity
relationship of 48 closely related N-benzyl phenethylamines as
5-HT2A/2C agonists. From that study, several interesting
Functional Pharmacology. Cell culturing, transfection, and
inositol phosphate turnover assay were adopted from a previously
published procedure.36
Cell Culture and Transfections. tsA201 cells (a transformed
HEK293 cell line) were cultured in GlutaMAX-I Dulbecco’s modified
Eagle’s medium (DMEM) supplemented with 10% dialyzed fetal
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
mL−1 BSA, pH 7.4) and preincubated in 100 μL assay buffer 1 for 4 h
at 37 °C, where the buffer was replaced after 2 h. The cells were then
Figure 7. Structure and in vitro pharmacological profile of 7b−9b and
10d−12d.
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washed and subsequently incubated in 50 μL of assay buffer 2 (HBSS
containing 1 mM CaCl2, 1 mM MgCl2, and 20 mM LiCl) for 30 min
at 37 °C. Following this incubation, the cells were stimulated with 50
μL of the indicated agonists in assay buffer 2 for 30 min at 37 °C.
The reactions were stopped by exchanging the buffer with 50 μL
ice-cold 10 mM formic acid and incubating the cells at 4 °C for at least
30 min. Yttrium silicate scintillation proximity assay beads (GE
Healthcare, Buckinghamshire, U.K.) were used for measuring
radioactivity from generated [3H]-IP essentially as previously
described.37 In brief, 20 μL of the formic acid cell extracts were
transferred to white 96-well plates, and 1 mg of yttrium silicate
scintillation proximity assay beads suspended in 80 μL water added to
each well. The plates were sealed, shaken vigorously for 1 h, and
centrifuged at 1500 rpm for 5 min. The radioactivity was quantified in
a Wallac Microbeta scintillation counter, and responses read as counts
per minute (CPM). All experiments were performed in triplicate and
repeated in at least three independent experiments.
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ASSOCIATED CONTENT
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■
S
* Supporting Information
NMR-data, including copies of H and 13C NMR spectra and
1
full details on the pharmacological characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
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Response of cluster headache to psilocybin and LSD. Neurology 66
(12), 1920−1922.
■
Corresponding Author
*Phone: +45 3533 6487. E-mail: jesper.kristensen@sund.ku.dk.
Author Contributions
J.K., M.H., M.B., and H.B.O. conceived the experiments. M.H.
and J.S.P. synthesized the compounds. M.H. and S.L.P.
characterized the compounds. K.P. and H.B.O. performed the
functional assays. M.H., S.L.P., and J.L.K. prepared the
manuscript.
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(2006) Psilocybin can occasion mystical-type experiences having
substantial and sustained personal meaning and spiritual significance.
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Funding
The Lundbeck foundation, the Danish Ministry of Science,
Innovation, and Higher Education and the The A. P. Møller
Foundation for the Advancement of Medical Sciences are
gratefully acknowledged for financial support.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Radioligand competition binding assay for affinity at human 5-
HT2A receptors and rat 5-HT2C receptors using displacement of
antagonist radioligands [3H]Ketanserin and [3H]Mesulergine
was 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, PhD at the University of
North Carolina at Chapel Hill and Project Officer Jamie Driscol
at NIMH, Bethesda MD.
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