Development of Highly Affine and Selective Fluorinated Cannabinoid Type 2 Receptor Ligands

Article abstract of DOI:10.1021/acsmedchemlett.7b00129

Cannabinoid type 2 receptors (CB₂ receptors) are involved in various pathological processes, and the visualization of their in vivo availability with positron emission tomography (PET) is of high interest. The study focuses on the introduction of fluorine into the structure of the highly affine and selective CB₂ receptor ligand N-(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5). A novel series of compounds was developed by modifying (i) the adamantane-3-position, (ii) the imidazole-N-phenyl ring, and (iii) the imidazole-2-position, and the impact on the CB₂ binding affinity and selectivity toward cannabinoid type 1 receptors (CB₁) was evaluated. This study identified compound 15 as one of the most potent (K_i(CB₂) = 0.29 nM) and selective (CB₁/CB₂ > 10000) CB₂receptor ligands discovered so far, eligible for the development of an¹⁸F-labeled PET radiotracer.

Full text of DOI:10.1021/acsmedchemlett.7b00129

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Letter
Development of highly affine and selective
fluorinated cannabinoid type 2 receptor ligands
Rare#-Petru Moldovan, Kristin Hausmann, Winnie Deuther-Conrad, and Peter Brust
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 28 Apr 2017
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ACS Medicinal Chemistry Letters
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Development of highly affine and selective fluorinated cannabinoid
type 2 receptor ligands
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Rareş-Petru Moldovan*, Kristin Hausmann, Winnie Deuther-Conrad, Peter Brust
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Helmholtz-Zentrum Dresden-Rossendorf e. V., Institute of Radiopharmaceutical Cancer Research, Permoserstraße
15, Leipzig 04318, Germany
KEYWORDS: Cannabinoid receptor type 2, Imidazole, Binding affinity, Fluorine, Positron emission tomography.
ABSTRACT: Cannabinoid type 2 receptors (CB2 receptors) are involved in various pathological processes, and the visuali-
zation of their in vivo availability with positron emission tomography (PET) is of high interest. The study focusses on the
introduction of fluorine into the structure of the highly affine and selective CB2 receptor ligand N-(adamantan-1-yl)-5-
ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5). A novel series of compounds was developed by modifying (i)
the adamantane-3-position, (ii) the imidazole-N-phenyl ring, and (iii) the imidazole-2-position, and the impact on the
CB2 binding affinity and selectivity towards cannabinoid type 1 receptors (CB1) was evaluated. This study identified com-
pound 15 as one of the most potent (Ki(CB2) = 0.29 nM) and selective (CB1/CB2 >10000) CB2 receptor ligands discovered so
far, eligible for the development of an 18F-labeled PET radiotracer.
Cannabis sativa and its extracts have been used for
centuries as therapeutic agent and recreational use.1 The
isolation and structure elucidation of the main psychoac-
injury (TBI), neurodegeneration, and apoptosis in several
cancer cell lines.12 Moreover, the neuroprotective role of a
CB2 receptor inverse agonist was demonstrated in a
mouse model of TBI.13
tive
constituent,
(−)-trans-Δ9-tetrahydrocannabinol
(THC, 1) by Mechoulam and co-workers2 led to the identi-
fication of the endocannabinoid system consisting of
neuromodulatory lipids and their (G-protein coupled)
receptors.3 Two types of cannabinoid receptors have been
well characterized so far, namely the cannabinoid recep-
tor type 1 (CB1 receptor)4 and the cannabinoid receptor
type 2 (CB2 receptor).5 Further receptors like GPR55 and
GPR18 are proposed to belong to the cannabinoid family.
However, the research on this subtypes is at early stage.6
CB1 receptors are located at neurons and their activation
is responsible for the psychotropic effect of 1. Recently,
the crystal structure of the CB1 receptors has been report-
ed facilitating future molecular modeling based drug
design and ligand optimization studies for this receptor
subtype.7 CB2 receptors are non-psychotropic, mainly
located peripherally and involved in several immune dis-
eases, neuropathic pain, and cancer.8 CB2 receptors are
also expressed at low levels in the healthy brain. The
physiological role of CB2 receptors in the brain has long
been controversially discussed.9
Recent evidence suggests that neuronal CB2 receptors
are involved in the regulation of hippocampal neuro-
transmission and in signaling pathways in the mouse
brain cortex via different Gα protein subunits.10 CB2 recep-
tors are able to form heteromers with other receptors
including CB1 (mainly post-synaptic) leading to new func-
tionalities and therefore new signaling pathways.11 In
pathological conditions, up-regulation of CB2 receptors
has been reported in association with traumatic brain
Figure 1. The structures of representative CB2 ligands.
In the past decades the development of selective CB2
receptor ligands was in the focus of medicinal chemistry
research.14, 15 However, despite the high number of ligands
specifically developed for this target, only a few com-
pounds were considered for clinical trials and none of
them has currently been approved for human use.11 When
targeting the cannabinoid receptors in the brain, the
predominantly disfavored pharmacological properties of
the CB2 ligands are caused by the hydrophobic nature of
the binding site of cannabinoid receptors suitable for
binding of the highly lipophilic natural ligands (e.g. 1,
LogD7.4 = 6.9). Unlike 1 which passes the blood-brain
barrier (BBB), most of the peripherally administered lipo-
philic substances do not and show high nonspecific bind-
ing to fat tissue.16 Profiling studies were performed to
identify ligands with the best molecular pharmacology for
targeting the CB2 receptors, which despite high lipophilic-
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ity are likely to reach the brain, mainly due to the low
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and its ability to tolerate fluoroderivatization needs to be
investigated especially due to the robustness and meta-
bolic stability of aryl fluorides.29 In parallel we decided to
introduce fluorine also at the imidazole-2-position and
check the influence on the CB2 receptor binding affinity.
Scheme 1. Synthesis of the lead 5 and derivative 8a
polar surface area.17 However, despite the promising ther-
apeutic and diagnostic potential the development of CB2
receptor ligands with improved neuropharmacological
properties remains a challenging task.
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5
6
7
8
The medicinal chemistry of the CB2 receptor ligands
covers various structural motifs.15 Beside the classical
tetrahydrocannabinol-derived cannabinoid ligands,18 N-
alkylindole-3-carboxamide is one of the most popular
building block of cannabinoid receptor ligands, and ef-
forts to develop CB2 receptor selective ligands proved to
be fruitful as shown by compound 2 (A-796260) in Figure
1.19 Quinoline is also a widely used scaffold for the devel-
opment of CB2 receptor ligands and representatively ex-
emplified in Figure 1 by compound 3 (JTE-907).20 Unlike
indoles, the quinoline type ligands generally possess high
selectivity towards the CB1 receptor. In the past years,
several 11C- and 18F-labeled ligands have been developed
for this scaffold21, 22 including [11C]NE40, the first and only
CB2 receptor radioligand which has been tested in hu-
mans to date.23 More recently, a novel series of pyrrole
and thiophene derived compounds has been reported,
some of them with high affinity for the CB2 receptor and
selectivity towards the CB1 receptors as exemplified by
compound 4 (Ki(CB2) = 2.15 nM, Ki(CB1) = 1008 nM).24
Consequently, the imaging properties of an 11C-labeled
analog of 4 have been investigated by in vitro and in vivo
autoradiography and PET studies by Haider and co-
workers.25
In our previous efforts to develop fluorinated CB2 re-
ceptor (radio)ligands we used oxazole, thiazole26 and
indole27 as scaffolds. Recently, we reported the develop-
ment of a highly affine and selective 18F-labeled CB2 radio-
tracer (Ki(CB2) = 0.4 nM, Ki(CB1) = 380 nM) and proved its
suitability in a mouse model of neuroinflammation,26
however, this radioligand suffers from low metabolic
stability in vivo. Here, we redirected our focus on the
structure of the highly affine and selective N-(adamantan-
1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-
R
O
O
O
N
(a)-(c)
(d)
O
O
N
H
N
N
9
O
N
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5, R = H
8, R = OH
6
7
aReagents and conditions: (a) NaNO2, AcOH/H2O, 0 °C to rt.,
2 h (77%); (b) H2, Pd/C, Ac2O, AcOH 1 atm., rt., 20 h (quanti-
tative); (c) aniline, TFA, butyronitrile, 117 °C, 1.5 h (24%); (d)
i. LiOH, H2O/MeOH, 70 °C, 5 h; ii. 1M HCl, rt.; iii. 1-
adamantylamine for 5 and 3-amino-1-hydroxyadamantane for
8, BOP, Et3N, DCM, rt., 20 h (30% over two steps).28
Scheme 2. Synthesis of adamantane functionalized
derivatives 9-11a
aReagents and conditions: (a) RX, NaH, DMF (9, 14%; 10,
19%; 11, 42%); (b) DAST, DCM, –78 °C to rt. (12, >90%).
The synthesis of the lead compound 5 and its hydrox-
yadamantane derivative 8 was performed as described
and depicted in Scheme 1 starting from the commercially
available methyl 3-oxopentanoate (6).28 Nitration of 6
gave the respective oxime which was further acetylated
with acetic anhydride under catalytic (H2, Pd/C) reductive
reactions conditions, followed by condensation with ani-
line in presence of TFA at elevated temperature and con-
cluded with cycloaromatization to imidazole 7. Ester
hydrolysis followed by Castro's reagent (BOP) mediated
amide bond formation with amantadine or 3-
aminoadamantan-1-ol as coupling partner delivered com-
pounds 5 and 8 respectively (Scheme 1).
carboxamide (5, Scheme 1).28 Compound 5 was reported
by Lange and co-workers28 as a result of a thorough SAR
study and its suitable pharmacological properties have
been highlighted (e.g.: CB1/CB2 >10000, MW = 349,
LogPHPLC = 3.5, PSA = 47).
With large amounts of 8 in our hands various reac-
tions conditions were investigated to etherify the alcohol
of the adamantine subunit. First, compound 8 was react-
ed with excess of MeI under deprotonative reaction con-
ditions (NaH) in DMF to provide 9 in 14% yield after 22
hours at room temperature. Large amounts of 8 remained
unreacted. The reaction yield could not be enhanced by
increasing the reaction time or the temperature. Attempts
to synthesize a fluoroethoxy or a fluoropropoxy analogue
by reacting the alcohol 8 with various electrophiles (e.g. 1-
fluoro-2-iodoethane, 1-fluoro-3-iodopropane, and the
corresponding mesylates and triflates) in presence of a
base (NaH up to 5 equivalents) failed in delivering the
desired ether presumably due to the low nucleophilicity
of the bulky alcohol combined with the volatility and
instability of the nucleophiles at elevated temperature.
However, the 1-fluorobuthoxy derivative 10 was synthe-
The aim of the presented work was the synthesis of a
fluorinated CB2 ligand based on the structure of com-
pound 5 (Scheme 1) as prerequisite for the development of
a novel 18F-labeled radiotracer for imaging of the cerebral
CB2 receptors with PET. The newly synthesized derivative
should retain the high CB2 affinity and selectivity of the
lead compound 5 and should contain a fluorine atom at a
position which allows a facile incorporation of 18F. Previ-
ous SAR studies performed on various CB2 ligands, in-
cluding the work which led to the identification of 528
highlighted the need of a lipophilic (e.g. tetramethylcy-
clopropyl, myrtanyl or adamantyl) subunit as pharmaco-
phore. However, recent studies showed the possibility to
hydroxylate the adamantane 3-position without loss of
affinity towards the CB2 receptors22, 25 opening the possi-
bility to fluoroalkoxylate this position of the molecule. On
the other side, the phenyl subunit has been less explored
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ACS Medicinal Chemistry Letters
sized in 19% yield by using 10 equivalents of 1-fluoro-4-
commercially available 16. In the first step, Chan-Lam
coupling resulted in formation of 17a (24% yield, together
with its regioisomer, 17b, 34% yield, Scheme 4),28 which
was then coupled with 1-adamantylamine to the amide 18,
and further selectively brominated with NBS at the se-
cond position to give 19. Bouveault reaction, using DMF
as reactant formed the respective aldehyde (20a) which
was smoothly reduced by NaBH4 in presence of MeOH to
give alcohol 20b. Compound 20b was converted by the
DAST mediated fluorodeoxygenation into the fluorome-
thyl derivative 21 in good yield and via Williamson ether
synthesis into the fluoroethoxy derivative 22.
1
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3
4
5
6
7
8
bromobutane at 80 °C for 22 hours. Benzylether 11 was
also synthesized according to this procedure (Scheme 2).
Furthermore, the DAST promoted fluorodeoxygena-
tion of 8 was performed to deliver 12 in nearly quantita-
tive yield. However, a “classical” (SN2) radiofluorination
procedure would not be applicable for the radiosynthesis
of [18F]12 and other methods would need to be developed.
It has previously been shown that both methyl and
ethyl substituents are well tolerated at the imidazole-2-
position without altering the binding affinity towards CB2
receptors and therefore, we redirected our attention at
this position in our efforts to introduce the fluorine atom.
Treatment of 5 with NBS under radical reactions condi-
tions employing AIBN delivered a complex reaction mix-
ture from which 13 was isolated in 30% yield. The low
yield and the difficult purification can be explained by the
competitive high reactivity of the imidazole-5-ethyl
group. Treatment of 13 with 2-fluoroethanol and 3-
fluoropropanol in presence of Cs2CO3, smoothly provided
ethers 14 and 15, respectively. Encouraged by these pre-
liminary results, we decided to develop an alternative,
more efficient method for the functionalization of imid-
azole at the 2-position. For this, we designed the 2-
bromoimidazole key intermediate 19 starting from the
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Scheme 3. Synthesis of imidazole-2-position func-
tionalized derivatives 14 and 15a
aReagents and conditions: (a) NBS, AIBN, CCl4, 77 °C, 6 h
(30%); (b) R-OH, Cs2CO3, MeCN, 40 °C, 60 min (>90%).
Scheme 4. Synthesis of imidazole-2-position functionalized derivatives 21 and 22a
aReagents and conditions: (a) C6H7BO2, CuI (cat.) EtOH/H2O, 85 °C, 60 h (17a, 24%, 17b, 34%); (b) 1-adamantylamine, AlMe3,
DCM, 35 °C (40% from 17a) (c) NBS, MeCN, rt., 4 h (85%); (d) i. LDA, THF, –78 °C, 30 min, ii. DMF, –78 °C to rt.; (e) NaBH4,
MeOH, 0 °C, 30 min (30% over two steps); (f) DAST, DCM, –78 °C, 30 min, 21, 91%; (g) 1-bromo-2-fluoroethane, DMF, NaH, 22,
83%.
Scheme 5. Synthesis of fluoroaryl compounds 26-28a
All the herein reported compounds were investigated
in vitro for their binding affinities towards the CB2 and
CB1 receptors according to a protocol well established in
our lab.26 For the CB2 assay, [3H](R)-(+)-[2,3-dihydro-5-
methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-
benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55.212-
2, 29) was used as competitive radioligand (KD = 2.1 nM)
together with increasing concentrations of the synthe-
sized (100 pM to 10 μM) on CHO cells stably transfected
with the human CB2 receptor (by courtesy of Prof. Pra-
ther, University Arkansas for Medical Sciences, Little
Rock, USA). The non-specific binding was determined by
using 10 μM [3H]29. The CB1 binding affinity was deter-
mined with hCB1-CHO obtained from Euroscreen,
Gosselies, Belgium and [3H](–)-cis-3-[2-hydroxy-4-(1,1-
dimethylheptyl)phenyl]-trans-4-(3-
aReagents and conditions: for (a)-(b) see Scheme 1; (c)
fluoroaniline, TFA, butyronitrile, 117 °C, 1.5 h (23, 12% yield;
24, 15% yield; 25, 18% yield); (d) 1-adamantylamine, AlMe3,
DCM, 35 °C, 22 h (26, 31 % yield; 27, 47% yield; 28, 33% yield).
To further explore the structural options of compound
5, the impact of the introduction of a fluorine atom at the
phenyl ring on the CB1/CB2 binding affinities was investi-
gated. Therefore, the three regioisomers 26, 27 and 28
were synthesized by using the corresponding fluoroan-
ilines (o-, m-, and p-, respectively) as source of fluorine by
using the same synthesis sequence as shown in Scheme 1.
Weinreb amidation employing AlMe3 delivered the
fluoroaryl derivatives 26-28 in moderate yield (Scheme 5,
3-5% yield over four steps).
hydroxypropyl)cyclohexanol (CP55.940, 30) as competi-
tive radioligand.26
As reflected by the Ki values in Table 1 the hydroxyla-
tion at the adamantane subunit in compound 5 led to a
drastic drop of affinity towards CB2 receptors proving the
need of a lipophilic partial structure at this site of the
molecule (compound 8).
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Table 1. In vitro binding affinity (Ki) at the human CB2 and CB1 receptors
1
2
3
4
5
6
7
8
9
Ki(CB2)
[nM]a
Ki(CB1)
[nM]a
R1
H
R2
R3
R4
Et
2.98 ± 0.33
(1.03 ± 0.2)b
101 ± 18.5
69.3 ± 15.7
13.9 ± 1.8
5
Me
Phenyl
>10000
8
OH
Me
Phenyl
Et
>1000
>10000
>10000
NA
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
OMe
Me
Phenyl
Et
10
11
O(CH2)4F
Me
Phenyl
Et
4-Fluorobenzyl ether
Me
Phenyl
Et
7.44 ± 1.0
1.0 ± 0.2
12
14
15
18
21
22
26
27
28
F
Me
Phenyl
Et
32620
7600
H
H
H
H
H
H
H
H
CH2O(CH2)2F
Phenyl
Et
1.1 ± 0.2
CH2O(CH2)3F
Phenyl
Et
0.29 ± 0.02
201 ± 16.5
4.16 ± 3.5
3.45 ± 0.6
5.56 ± 0.28
3.41 ± 0.18
10.2 ± 0.2
>10000
>10000
5000
H
Phenyl
Me
Me
Me
Et
CH2F
Phenyl
CH2O(CH2)2F
Phenyl
9200
Me
Me
Me
2-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
>10000
>10000
>10000
Et
Et
aMeans (±) of two to three experiments run in triplicate; bKi of compound 5 as reported in 28; NA = not available.
This was, however, rather unexpected when compared
with the related quinoline-2-one-3-carboxamide22 thio-
phene-2-carboxamide derived CB2 receptor ligands, for
tor. Considering this, the implementation of a 2-
fluoropyridin subunit at this position (not described)
might be tolerated too affording ligands with enhanced
eligibility for aromatic radiofluorination. Notably, for all
the herein reported derivatives the CB1 receptor affinity
remained constantly low (>1 µM).
25
which the hydroxylation of the adamantan subunit was
tolerated without loss of binding affinity. Methoxylation
at this position led to a slight increase in affinity whereas
butoxylation nearly restored the low-nanomolar binding
affinity of the starting compound 5 profiling the lipo-
philicity dependent binding mode towards the CB2 recep-
tor. Additionally, the implementation of the 4-
fluorobenzyl as substituent at this position further im-
proved the binding affinity towards the CB2 receptors.
Replacement of the hydroxyl group by fluorine yielded
derivative 12 which slightly surpassed the low-nanomolar
affinity of the lead molecule with a Ki value of 1 nM.
Derivatization performed at the imidazole-2-position
revealed the distinct need of a substituent, as proven by
the low CB2 binding affinity of the non-substituted com-
pound 18 (Table 1).
Accordingly, the binding data of imidazole-2-
fluoromethyl derivative 21 correlated with the low-
nanomolar CB2 affinity of the lead compound 5. The in-
troduction of an ether function and simultaneous chain
elongation at this position did not considerably alter the
binding affinity as demonstrated by the imidazole-2-
fluoroethoxylated compounds 14 and 22. Notably, the use
of a fluoropropoxy ether at this part of the molecule en-
hanced the binding affinity towards the CB2 receptors to
sub-nanomolar level (0.29 nM, Table 1). Furthermore, the
three fluorophenyl regioisomers (26, 27 and 28 respective-
ly) possess high CB2 affinity (Ki(CB2) ≤10 nM) and CB1/CB2
selectivity (>1000) revealing a moderate influence of the
phenyl ring on the ligand binding mode to the CB2 recep-
In summary, a novel series of CB2 fluorinated 1-aryl-
imidazole-4-yl-carboxamide CB2 receptor ligands has
been synthesized by varying the 1-aryl subunit, the imid-
azole 2-position, and the adamantane. First in vitro inves-
tigations revealed a moderate tolerability of an ether
function at the adamantane subunit with a binding affini-
ty towards the CB2 receptor in good correlation with the
lipophilicity of the alkoxy group. On the other hand the
introduction of the fluorine at the phenyl ring has only a
minor impact on the CB2 receptor binding affinity. De-
spite the unfavorable electron density for an SN2 substitu-
tion, the radiofluorination at this position might be pos-
sible due to the recent developments in the methodology
of the late-stage 18F-labeling.30 However, the implementa-
tion of more suitable surrogates at this subunit (e.g. 2-
fluoropyridine) needs to be considered. The most suitable
position for fluoroderivatization was discovered to be the
imidazole position-2. As
a
result, the 2-(3-
fluoropropoxy)methyl-1H-imidazole derivative 15 was
identified with sub-nanomolar binding affinity (Ki = 0.29
nM) combined with an excellent selectivity against the
CB1 receptor subtype (CB1/CB2 >10000).
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org and includes detailed experimental pro-
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1
10.
Kendall, D. A.; Yudowski, G. A. Cannabinoid receptors
cedures, compounds characterization and H NMR of final
in the central nervous system: their signaling and roles in dis-
ease. Front. Cell. Neurosci. 2017, 10: 294.
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2
3
4
5
6
7
8
compounds.
11.
Navarro, G.; Morales, P.; Rodríguez-Cueto, C.; Fernán-
AUTHOR INFORMATION
Corresponding Author
dez-Ruiz, J.; Jagerovic, N.; Franco, R. Targeting cannabinoid CB2
receptors in the central nervous system. Medicinal chemistry
approaches with focus on neurodegenerative disorders. Front.
Neurosci. 2016, 10:406.
* Rareş-Petru Moldovan Tel.: +49-341-234179-4634; fax: +49-
341-234179-4699; e-mail: r.moldovan@hzdr.de.
12.
Giacoppo, S.; Mandolino, G.; Galuppo, M.; Bramanti,
Author Contributions
P.; Mazzon, E. Cannabinoids: new promising agents in the
treatment of neurological diseases. Molecules 2014, 19, 18781-
18816.
9
R.-P. M. designed the study. R.-P. M. and K.H. conceived and
performed the chemical syntheses. W. D.-C. and P. B.
planned and performed the radioligand binding studies. All
authors contributed to and approved the final version of the
manuscript.
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Bu, W.; Ren, H.; Deng, Y.; Del Mar, N.; Guley, N. M.;
Moore, B. M.; Honig, M. G.; Reiner, A. Mild traumatic brain
injury produces neuron loss that can be rescued by modulating
microglial activation using a CB2 receptor inverse agonist. Front.
Neurosc. 2016, 10:449.
Funding Sources
14.
Morales, P.; Hernandez-Folgado, L.; Goya, P.; Jagero-
Financial support has been obtained from Helmholtz-
Zentrum Dresden-Rossendorf.
vic, N. Cannabinoid receptor 2 (CB2) agonists and antagonists: a
patent update. Expert Opin. Ther. Patents 2016, 26, 843-856.
15.
Aghazadeh Tabrizi, M.; Baraldi, P. G.; Borea, P. A.; Va-
ACKNOWLEDGMENT
rani, K. Medicinal chemistry, pharmacology, and potential ther-
apeutic benefits of cannabinoid CB2 receptor agonists. Chem.
Rev. 2016, 116, 519-560.
We thank Mrs. Tina Spalholz for help with radioligand bind-
ing studies, and Dr. Matthias Scheunemann and Marcel
Lindemann for scientific discussions; Marcel Lindemann
helped with the HPLC purity determinations. We thank the
staff of the Institute of Analytical Chemistry, Department of
Chemistry and Mineralogy of the Universität Leipzig, for the
MS and NMR spectra.
16.
Pajouhesh, H.; Lenz, G. R. Medicinal chemical proper-
ties of successful central nervous system drugs. NeuroRx. 2005,
2, 541-553.
17.
Soethoudt, M.; Grether, U.; Fingerle, J.; Grim, T. W.;
Fezza, F.; de Petrocellis, L.; Ullmer, C.; Rothenhausler, B.; Perret,
C.; van Gils, N.; Finlay, D.; MacDonald, C.; Chicca, A.; Gens, M.
D.; Stuart, J.; de Vries, H.; Mastrangelo, N.; Xia, L.; Alachouzos,
G.; Baggelaar, M. P.; Martella, A.; Mock, E. D.; Deng, H.; Heit-
man, L. H.; Connor, M. Cannabinoid CB2 receptor ligand profil-
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ABBREVIATIONS
AA, ammonium acetate; CB2, cannabinoid receptors type 2;
CB1, cannabinoid receptors type 1; PET, positron emission
tomography; DMF, N,N-dimethylformamide; BOP, (Ben-
zotriazol-1-yloxy)tris(dimethylamino)phosphonium
afluorophosphate; Et3N, triethylamine; CHO, chinese ham-
ster ovary; EA, ethyl acetate; PE, Petroleum ether (35-60 °C).
18.
Bow, E. W.; Rimoldi, J. M. The structure–function rela-
hex-
tionships of classical cannabinoids: CB1/CB2 modulation. Per-
spect. Medicin. Chem. 2016, 8, 17-39.
19.
Eissenstat, M. A.; Bell, M. R.; D'Ambra, T. E.; Alexan-
der, E. J.; Daum, S. J.; Ackerman, J. H.; Gruett, M. D.; Kumar, V.;
Estep, K. G. Aminoalkylindoles: structure-activity relationships
of novel cannabinoid mimetics. J. Med. Chem. 1995, 38, 3094-
3105.
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