Affinity of?1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives to?the?ion channel binding site of?the?NMDA receptor complex

Article abstract of DOI:10.1016/j.ejmech.2006.03.005

A series of 1-aryl-1,2,3,4-tetrahydroisoquinoline and 8-methyl-1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives was evaluated for affinity to the PCP binding site of the NMDA receptor complex. The (S)-configurated tetrahydroisoquinoline derivative (S)-4e·HCl bearing a 2-methylphenyl substituent in position 1 of the heterocyclic ring system and a methyl group in position 8 was found to exhibit the highest affinity among the derivatives with a K_i-value of 0.0374?μM. In addition, this compound shows a remarkable enantioselectivity of binding by being almost 90 times more potent than the corresponding (R)-enantiomer (R)-4e·HCl. Additionally, a convenient and efficient synthetic approach to racemic 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives is described.

Full text of DOI:10.1016/j.ejmech.2006.03.005

European Journal of Medicinal Chemistry 41 (2006) 1003–1010
http://france.elsevier.com/direct/ejmech
Short communication
Affinity of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives
to the ion channel binding site of the NMDA receptor complex
Matthias Ludwig a, Cornelia E. Hoesl b, Georg Höfner b, Klaus T. Wanner b,*
a Selectavet Dr. Otto Fischer GmbH, Am Kögelberg 5, 83629 Weyarn-Holzolling, Germany
b Department Pharmazie – Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany
Received in revised form 10 March 2006; accepted 17 March 2006
Available online 03 May 2006
Abstract
A series of 1-aryl-1,2,3,4-tetrahydroisoquinoline and 8-methyl-1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives was evaluated for affinity to
the PCP binding site of the NMDA receptor complex. The (S)-configurated tetrahydroisoquinoline derivative (S)-4e·HCl bearing a 2-methylphe-
nyl substituent in position 1 of the heterocyclic ring system and a methyl group in position 8 was found to exhibit the highest affinity among the
derivatives with a Ki-value of 0.0374 μM. In addition, this compound shows a remarkable enantioselectivity of binding by being almost 90 times
more potent than the corresponding (R)-enantiomer (R)-4e·HCl. Additionally, a convenient and efficient synthetic approach to racemic 1-aryl-
1,2,3,4-tetrahydroisoquinoline derivatives is described.
© 2006 Elsevier SAS. All rights reserved.
Keywords: N-Methyl-D-aspartate receptor; PCP binding site; MK-801; Tetrahydroisoquinolines
1. Introduction
by antagonizing the ionotropic L-glutamate receptor N-
methyl-D-aspartate (NMDA) limits cascades of neurotoxicity
thereby impeding neuronal damage. A blockade of the NMDA
receptor complex also efficiently suppresses central sensitiza-
tion to pain occurring due to prolonged firing of C-fiber noci-
ceptors and enhanced release of glutamate [3]. Since NMDA
antagonists have been found to effectively counteract opioid
tolerance, they are potentially advantageous as coanalgesics
in combination with opioids [4].
Most excitatory synapses in the brain use the neurotransmit-
ter glutamate to pass on impulses between neurons. Glutama-
tergic pathways are ubiquitous throughout the brain and phy-
siological short-term glutamate release is crucial to synaptic
plasticity and higher brain functions such as learning and mem-
ory [1]. Excessive exposure to glutamate, conversely, causes
overstimulation of the various glutamate receptors leading to
localized vulnerability of neurons and triggering neuronal cell
death. This excitotoxicity resulting from glutamate exceeding
physiological levels is one of the key factors contributing to
acute and chronic neuropathological processes, such as ische-
mia, traumatic brain injury, epilepsy, Parkinson’s, Hunting-
ton’s, and Alzheimer’s disease, whereas deficient glutamater-
gic neurotransmission might be connected with schizophrenia
[2]. Modulation of the excitatory synaptic neurotransmission
Antagonism of receptor mediated processes can be achieved
pharmacologically by interaction with the various binding sites
of the NMDA receptor complex, i.e. the glutamate-binding
site, the glycine co-agonist site, the polyamine binding site,
and the redox modulatory site(s) [5]. Lodge et al. identified
phencyclidine (PCP) as a noncompetitive NMDA antagonist
binding to a previously unknown discrete site located within
the cation channel thereby impeding ion passage through the
open-channel [6]. The discovery laid the foundation for inten-
sive research towards so called open-channel blockers acting at
this PCP binding site. MK801 (1), one of the most potent li-
gands, serves as an excellent probe for the evaluation of novel
NMDA channel blockers (Fig. 1). Efforts to develop NMDA
antagonists have been plagued by the need to weigh the clin-
Abbreviations: CC, column chromatography; GP, general procedure;
NMDA, N-methyl-D-aspartate; PCP, phencyclidine; S.E.M., standard error of
the means.
* Corresponding author. Tel.: +49 89 2180 77249; fax: +49 89 2180 77247.
E-mail address: Klaus.Wanner@cup.uni-muenchen.de (K.T. Wanner).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.03.005

1004
M. Ludwig et al. / European Journal of Medicinal Chemistry 41 (2006) 1003–1010
Fig. 1. Structures of representative known NMDA receptor antagonists acting at the PCP binding site.
ical benefits against possible side effects. The therapeutic value
of a range of NMDA antagonists is compromised by side ef-
fects including psychosis, agitation, and disorientation. Ap-
proved open-channel blockers include memantine, amantadine,
budipine, ketamine and dextromethorphane. Gray et al. [7] dis-
covered that 1-phenyl-1,2,3,4-tetrahydroisoquinoline (2) dis-
plays high affinity to the PCP binding site. As demonstrated
in our group, binding of the (S)-enantiomer is 27-fold greater
than that of the (R)-enantiomer (Fig. 1) [8]. Consistently, the
potency of the (S)-configurated close analogue FR115427 (3)
was found to differ from its enantiomer exceeding it by a factor
of 100 (Fig. 1) [9].
allylic strain and thereby the position of the conformational
equilibrium will also depend on the steric demand of the sub-
stituent present in position 1. Therefore, when the 1-phenyl
group in 4a and 4d is replaced by sterically more demanding
residues, as in 4b–c and 4e–f, this should also affect the posi-
tion of the conformational equilibria and raise the amount of
the conformer with the 1-aryl substituent adopting a pseudo
axial position.
Conformational changes like this can be expected to have a
marked influence on the capability of the individual com-
pounds for binding to the target site. Therefore, we thought it
quite promising to study the affinity of 4a–f to the PCP binding
site of the NMDA receptor.
Herein we report the biological evaluation of the 1-aryl-
1,2,3,4-tetrahydroisoquinolines 4a–c·HCl and the correspond-
ing 8-methyl derivatives 4d–f·HCl in their racemic form and,
for most though not all of the compounds, their enantiomeri-
cally pure form as well (Fig. 2). The conceptual rationale for
the introduction of a methyl substituent in position 8 was to
utilize the A(1,3) strain [10] to change the conformation of the
corresponding compound. Based on a conformational analysis
performed for closely related isoquinoline derivatives [11] it is
reasonable to assume that the preferential conformation
adopted by tetrahydroisoquinoline 4a is one where the hetero-
cyclic ring exists as a half chair and the phenyl ring is disposed
in a pseudo equatorial position. But this conformation is likely
to change when a methyl group is introduced in position 8 of
the isoquinoline nucleus. The severe increase in of the A(1,3)
strain between the substituents in positions 1 and 8 of the tetra-
hydroisoquinoline nucleus resulting from the newly introduced
methyl substituent can be expected to force the phenyl group
present in position 1 out of the plane of the heterocyclic ring
system into a pseudo axial position. Of course, the extent of the
Additionally, we describe in this paper a highly efficient
procedure which provides a straightforward access to the iso-
quinoline derivatives 4a–f·HCl in racemic form. The procedure
is based on N-acyliminium ion chemistry and complements
earlier efforts directed towards the synthesis of 4a–f·HCl in
enantiopure form by a related but asymmetric strategy [12].
For the sake of simplicity the evaluation of the biological ac-
tivity potencies of 4a–f·HCl at the PCP binding site of the
NMDA receptor was based on the racemic compounds, as
most but not all of the desired tetrahydroisoquinoline deriva-
tives 4a–f·HCl had been accessible by the aforementioned
asymmetric synthesis in enantiopure form.
2. Chemistry
The trapping reaction of N-acyliminium ions with nucleo-
philes is a well established procedure for the construction of
α-substituted amides and carbamates as well as their corre-
Fig. 2. The structures of the target compounds.

M. Ludwig et al. / European Journal of Medicinal Chemistry 41 (2006) 1003–1010
1005
sponding amines [13]. We conjectured that this powerful meth-
od could be suitable to conveniently provide the racemic 1-
aryl-1,2,3,4-tetrahydroisoquinoline derivatives rac-4·HCl
(Scheme 1). Compounds 6, easily obtained by reaction of tetra-
hydroisoquinoline derivatives 5 [14] and benzyl chloroformate
(yield: 89–95%), proved to be a well-suited precursors for the
generation of the isoquinolinium ions 7. Direct reaction of an
imine or an N-heterocycle with acylchlorids or chloroformates
often suffers from an unfavorable equilibrium. Generation of
N-acyliminium ions by hydrid abstraction from compounds 6
synthesis based on chiral N-acyliminium ion as mentioned
above [12].
3. Results and discussion
The water soluble hydrochloride salts rac-4a–f·HCl, (S)-
4a·HCl, (S)-4d–f·HCl, (R)-4a·HCl, (R)-4c·HCl and (R)-4e–
f·HCl were screened for their in vitro activity at the PCP site
of the NMDA receptor complex using a competitive binding
assay at pig frontal cortex preparations with the radioligand
[3H]MK-801 that binds to and blocks the channel pore mostly
when the receptor is in its active conformation. MK-801 served
as reference compounds and exhibited a Ki-value of 1.26
0.18 nM. The biological activities of 1-phenyl-1,2,3,4-tetra-
hydroisoquinolines (S)-4a·HCl and (R)-4a·HCl assessed in a
radioreceptor binding assay based on rat frontal cortex were
already reported in literature [8] [(S)-4a·HCl: Ki = 1.38
0.07 μM and (R)-4a·HCl: Ki = 37.9 5.4 μM]. Using pig
frontal cortex we found slightly different Ki values (rac-
4a·HCl: Ki = of 0.921 0.021 μM, (S)-4a·HCl: Ki = 0.553
0.026 μM, and (R)-4a·HCl: Ki = 32.17 1.24 μM). Introduc-
tion of a methyl group at position 8 of the isoquinoline ring to
force the 1-aryl moiety into a pseudo axial position by enhan-
using Ph3C+BF4 as oxidizing reagent was found to be advan-
–
tageous since it is an irreversible process leading to almost
complete formation of the key intermediates 7 [8,15,16]. Addi-
tion of the respective Grignard reagent (PhMgCl, 2-methylphe-
nylmagnesium bromide, 2,6-dimethylphenylmagnesium bro-
mide) to the N-acyliminium ions 7 proceeded with moderate
yields (56–71%). The final racemic compounds rac-4a–f·HCl
needed for the biological studies were obtained by removal of
the carbamate functionality employing catalytic hydrogenolysis
(H2, Pd/C) and subsequent treatment with hydrogen chloride
(yields: 46–91%). In addition to these racemic compounds the
pure enantiomers (S)-4a·HCl, (S)-4d–f·HCl, (R)-4a·HCl, (R)-
4c·HCl and (R)-4e–f·HCl were available to us, too. Their
synthesis had been accomplished by an analogous asymmetric
Scheme 1. Synthetic approach to racemic 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives.

1006
M. Ludwig et al. / European Journal of Medicinal Chemistry 41 (2006) 1003–1010
Table 1
ESSAI Affinity of compounds 4·HCl to the PCP binding site of the NMDA receptor complex
Ki-value (μM)
R1
H
R2
0.921 0.021
0.553 0.026
32.17 1.24
(rac-4a·HCl)
((S)-4a·HCl)
((R)-4a·HCl)
0.514 0.039
(rac-4b·HCl)
–
–
–
–
7.52 0.20
(rac-4c·HCl)
5.97 0.29
((R)-4c·HCl)a
CH3
0.872 0.063
(rac-4d·HCl)
0.475 0.030
((S)-4d·HCl)
0.0827 0.0097
0.0374 0.0068
3.31 017
(rac-4e·HCl)
((S)-4e·HCl)
((R)-4e·HCl)
1.87 0.25
1.06 0.06
5.81 0.34
(rac-4f·HCl)
((S)-4f·HCl)
((R)-4f·HCl)
a
Of note: for R1 = H and R2 = 2,6-(CH3)2C6H3 (4c) the stereochemical descriptor changes due to the higher priority of the 2,6-(CH3)2C6H3 moiety.
cing the allylic strain led to higher potencies for compounds
rac-4e–f·HCl at the PCP binding site as compared to the 8-
unsubstituted derivatives rac-4b–c·HCl (Table 1). rac-4a and
rac-4d also seem to follow the same trend, but in this case the
difference between the Ki values is not significant. Among the
series of the racemic mixtures, the 1-tolyl substituted deriva-
tives rac-4b·HCl and rac-4e·HCl exhibited the highest affi-
nity, with Ki-values of 0.514 0.039 and 0.0827
0.0097 μM, respectively. In contrast, replacement of the tolyl
group by a xylyl moiety was found to be detrimental, leading
to a profound loss of affinity with compounds rac-4c·HCl and
rac-4f·HCl exhibiting the highest Ki values (Table 1).
rac-4f·HCl, respectively, are not. This could explain the higher
potency of rac-4e·HCl compared to that of rac-4d·HCl and
rac-4f·HCl, though other phenomena of a more steric origin,
an attractive interaction with the target binding site for the first
ortho methyl group (in rac-4e·HCl) and a repulsion of the sec-
ond (in rac-4f·HCl) could be responsible as well.
It has consistently been noted that 1-aryl-1,2,3,4-tetrahy-
droisoquinolines display a distinct enantioselectivity of binding
with the (S)-configurated enantiomer being more potent than its
counterpart [8,9]. This observation is confirmed by the screen-
ing data reported here (see Table 1). Overall, methyl substitu-
tion at position 8 of the isoquinoline ring, one methyl group in
o-position of the 1-phenyl moiety and (S)-configuration gave
the most potent compound (S)-4e·HCl with a Ki-value
of = 0.0374 0.0068 μM. The pharmacological enantioselec-
tivity was determined to be 89/1 ((S)-4e·HCl/(R)-4e·HCl) al-
most reaching the eudismic ratio reported for 3 (100/1) [9].
So far one can only speculate about the origin of the high
affinity of rac-4e·HCl to the PCP binding site compared to the
remaining racemates. However, the presence of a methyl sub-
stituent at position 8 of the isoquinoline ring, as for example in
rac-4d–f·HCl, will certainly cause a marked change of the con-
formational equilibrium of these compounds, forcing the aryl
substituent at position 1 out of the ring plane into a more pseu-
do axial orientation. The ortho substituents at the phenyl ring
of rac-4e–f·HCl will, furthermore, effect the rotational isomer-
ism around the single bond between C-1 of the isoquinoline
moiety and the quaternary carbon of the aryl ring. The 1-tolyl
group in rac-4e could be capable of favoring a specific confor-
mation that is beneficial for binding to the target whereas the
symmetric 1-phenyl and 1-xylyl moieties in rac-4d·HCl and
4. Conclusion
In summary, we have developed a new method for the
synthesis of 1-aryl-1,2,3,4-tetrahydroisoquinolines. Biological
screening showed that a methyl group in position 8 and the
o-position of the 1-phenyl substituent is beneficiary for binding
affinity to the PCP site of the NMDA receptor complex. Our
results corroborate previous findings that the potency of 1-aryl-

M. Ludwig et al. / European Journal of Medicinal Chemistry 41 (2006) 1003–1010
1007
1,2,3,4-tetrahydroisoquinolines to the PCP binding site is
5.1.4. Catalytic hydrogenolysis (GP3)
highly enantioselective.
20% Pd/C (oxidized form, 1.0 w/w) were added to the re-
spective compound 8 (0.2 M in MeOH) in a 3-necked round-
bottom flask connected to a gas burette and the reaction mix-
ture was hydrogenated at room temperature and normal
pressure for 16 h. Following filtration and evaporation in va-
cuo, the free amines were obtained. Treatment of the free
amines in Et2O with gaseous HCl and evaporation in vacuo
gave the corresponding hydrochlorides 4·HCl.
5. Experimental
5.1. Chemistry
5.1.1. General
All reactions were carried out in vacuum dried glassware
under nitrogen atmosphere. All reagents were used as commer-
cially available. PhMgCl was purchased from Fluka (1.8 M in
THF). 2-Methylphenylmagnesium bromide and 2,6-dimethyl-
phenylmagnesium bromide were prepared from 2-bromoto-
luene and from 2-bromo-1,3-dimethylbenzene in THF, respec-
tively (1.0 M in THF based on amount of arylhalide employed,
metallic magnesium was activated by means of I2). Solvents
were dried and distilled prior to use. CH2Cl2 was distilled from
CaH2 and CH3OH from Mg prior to use. Melting points were
determined on a Büchi melting point apparatus no. 510 (Dr.
Tottoli) and are uncorrected. IR spectra were recorded with a
Perkin Elmer FT-IR spectrophotometer Paragon 1000 or 1600,
and NMR spectra were obtained with a JEOL JNM-GX 400
spectrometer (400 MHz for 1H, 100 MHz for 13C) with
TMS as internal standard. The NMR spectra were recalculated
with NUTS, 2D version 4.35 or 5.097. MS spectra were re-
corded on a Hewlett Packard 5989 A with 59980 B particle
beam LC/MS interface. CHN-analyses were determined with
an elemental analysator Rapid (Heraeus). The results of ele-
mental analyses for C, H and N were within 0.4% of the
theoretical values. LC: Merck 60 F-254. Column chromatogra-
phy (CC) was performed as flash chromatography with silica
gel Merck 60 F-254 (0.040−0.063 mm).
5.1.5. N-Benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline
(6a)
According to GP1 from benzylchloroformate (5.16 ml,
36.13 mmol), 1,2,3,4-tetrahydroisoquinolinium hydrochloride
5a·HCl) (4.087 g, 24.09 mmol) and NEt3 (10.07 ml,
72.27 mmol) in 50 ml CH2Cl2; reaction time: 17 h. Purification
by CC (EtOAc/n-heptane = 20:80). Yield: 5.713 g (89%); col-
orless oil. TLC: Rf = 0.42 (EtOAc/n-heptane = 20:80). 1H
NMR (CDCl3, 20 °C): δ = 2.77−2.95 (m, 2 H, CH2CH2),
3.63−3.81 (m, 2 H, CH2CH2), 4.67 (s, 2 H, CarCH2N), 5.20
(s, 2 H, CH2O), 7.06−7.24 (m, 4 H, Haromat), 7.30−7.45 (m, 5
H, Haromat).
5.1.6. N-Benzyloxycarbonyl-8-methyl-1,2,3,4-
tetrahydroisoquinoline (6b)
According to GP1 from benzylchloroformate (0.87 ml,
6.06 mmol), 8-methyl-1,2,3,4-tetrahydroisoquinoline (5b) [14]
(1.173 g, 4.04 mmol) and NEt3 (1.69 ml, 12.13 mmol) in 14 ml
CH2Cl2; reaction time: 18 h. Purification by CC (EtOAc/n-hep-
tane = 15:85). Yield: 1.077 g (95%); colorless oil. TLC: Rf
1
= 0.40 (EtOAc/n-heptane = 15:85). H NMR (CDCl3, 20 °C):
δ = 2.17−2.29 (m, 3 H, CarCH3), 2.85 (br. s, 2 H, CH2), 3.68
−3.76 (m, 2 H, CH2), 4.55 (s, 2 H, CarCH2N), 5.20 (s, 2 H,
CH2O), 6.95−7.01 (m, 1 H, Haromat), 7.03 (d, J = 7.4 Hz, 1 H,
Haromat), 7.09 (t, J = 7.4 Hz, 1 H, Haromat), 7.29−7.42 (m, 5 H,
5.1.2. Synthesis of the N-benzyloxycarbonyl-1,2,3,4-
tetrahydroisoquinolines (GP1)
−1
~
Haromat). IR (film): n = 1700 cm , 1429, 1286, 1246, 1219.
MS (CI); m/z (%): 282 (100) [M + H+], 190 (36), 174 (13),
Benzyl chloroformate was added to a solution of the respec-
tive 1,2,3,4-tetrahydroisoquinoline 5 and NEt3 in CH2Cl2. The
reaction mixture was stirred at room temperature. After addi-
tion of HCl (2 M in H2O) the organic solvent was evaporated
in vacuo. Following extraction with Et2O, the organic layers
were dried (MgSO4), concentrated in vacuo, and purified by
CC.
91 (55). C18H19NO2 (281.36).
5.1.7. N-Benzyloxycarbonyl-1-phenyl-1,2,3,4-
tetrahydroisoquinoline (rac-8a)
According to GP2 from compound 6a (1.068 g, 3.00 mmol)
and PhMgCl (1.8 M in THF, 6.66 ml, 11.98 mmol). Purifica-
tion by CC (Et2O/n-heptane = 20:80). Yield: 0.928 g (68%);
colorless oil. TLC: Rf = 0.23 (Et2O/n-heptane = 20:80). 1H
NMR (d5-nitrobenzene, 140 °C): δ = 2.78 (dt, J = 16.1, 5 Hz,
1 H, CH2CH2), 2.95 (ddd, J = 16.1, 9.7, 5 Hz, 1 H, CH2CH2),
3.44 (ddd, J = 13.2, 9.7, 4.8 Hz, 1 H, CH2CH2), 4.13 (dt,
J = 13.2, 5 Hz, 1 H, CH2CH2), 5.28 (d, J = 12.7 Hz, 1 H,
CH2O), 5.35 (d, J = 12.7 Hz, 1 H, CH2O), 6.47 (s, 1 H, CH),
7.05 (d, J = 7.5 Hz, 1 H, Haromat), 7.12−7.35 (m, 11 H,
5.1.3. α-Amidoalkylation via N-benzyloxycarbonyliminium ions
(GP2)
Ph3C+BF4 (1.1 eq, 0.1 M in CH2Cl2) was added to a solu-
−
tion of 6 (0.03 M in CH2Cl2) at room temperature. After 16 h
the reaction mixture was cooled to –78 °C followed by the
addition of the respective Grignard reagent. The reaction was
quenched with H2O after 4 h, warmed to room temperature,
and acidified with HCl (2 M in H2O). Following extraction
with Et2O, the combined organic layers were dried (MgSO4),
concentrated in vacuo, and purified by CC.
~
Haromat), 7.39−7.44 (m, 2 H, Haromat). IR (film): n =
1698 cm−1, 1454, 1425, 1293, 1227. MS (CI); m/z (%): 344
(100) [M + H+], 266 (12), 252 (22), 208 (5). C23H21NO2
(343.43).

1008
M. Ludwig et al. / European Journal of Medicinal Chemistry 41 (2006) 1003–1010
5.1.8. N-Benzyloxycarbonyl-1-(2-methylphenyl)-1,2,3,4-
tetrahydroisoquinoline (rac-8b)
Yield: 0.441 g (71%); colorless crystals. TLC: Rf = 0.14
(CH2Cl2/n-heptane = 80:20). M.p. 140 °C. H NMR (d5-nitro-
1
According to GP2 from compound 6a (0.514 g, 1.92 mmol)
and 2-methylphenylMgBr (1.0 M in THF, 5.77 ml, 5.77 mmol).
Purification by CC (EtOAc/n-heptane = 10:90). Yield: 0.434 g
benzene, 140 °C): δ = 1.93 (s, 3 H, CH3), 2.59 (s, 3 H, CH3),
2.71−2.79 (m, 1 H, CH2CH2), 3.08−3.27 (m, 2 H, CH2CH2),
4.09−4.17 (m, 1 H, CH2CH2), 5.27−5.35 (m, 2 H, CH2O), 6.69
(d, J = 7.9 Hz, 1 H, Haromat), 6.79 (s, 1 H, CH), 6.92−7.05 (m,
(63%);
colorless
oil.
TLC:
Rf = 0.21
(EtOAc/n-
heptane = 10:90). 1H NMR (d5-nitrobenzene, 140 °C):
δ = 2.58 (s, 3 H, CH3), 2.83 (ddd, J = 16.4, 4.2, 2.5 Hz, 1 H,
CH2), 3.06 (ddd, J = 16.4, 11.5, 6.2 Hz, 1 H, CH2), 3.42 (ddd,
J = 13.6, 11.5, 4.2 Hz, 1 H, CH2), 4.27 (ddd, J = 13.6, 6.2,
2.5 Hz, 1 H, CH2), 5.23 (d, J = 12.5 Hz, 1 H, CH2O), 5.27
(d, J = 12.5 Hz, 1 H, CH2O), 6.59 (s, 1 H, CH), 6.87 (d,
J = 7.7 Hz, 1 H, Haromat), 6.91 (d, J = 7.7 Hz, 1 H, Haromat),
3 H, Haromat), 7.09−7.34 (m, 6 H, Haromat), 7.41 (d, J = 7.9 Hz,
−1
~
2 H, Haromat). IR (KBr): n = 1698 cm , 1436, 1412, 1214,
1104. MS (CI); m/z (%): 372 (56) [M + H+], 280 (27), 236
(8), 167 (100). C25H25NO2 (371.48).
5.1.12. N-Benzyloxycarbonyl-1-(2,6-dimethylphenyl)-8-methyl-
1,2,3,4-tetrahydroisoquinoline (rac-8f)
According to GP2 from compound 6b (0.680 g, 2.42 mmol)
and 2,6-dimethylphenylMgBr (1.0 M in THF, 7.25 ml,
7.25 mmol). Purification by CC (EtOAc/n-heptane = 10:90).
Yield: 0.453 g (69%); colorless oil. TLC: Rf = 0.18 (CH2Cl2/
n-heptane = 50:50). 1H NMR (d5-nitrobenzene, 140 °C):
δ = 1.93 (s, 3 H, CH3), 2.15 (br. s, 6 H, 2 × CH3), 2.72−2.84
(m, 1 H, CH2), 3.24−3.37 (m, 2 H, CH2), 4.13−4.25 (m, 1 H,
CH2), 5.27 (s, 2 H, CH2O), 6.80 (s, 1 H, CH), 6.91−7.00 (m, 4
H, Haromat), 7.04−7.11 (m, 2 H, Haromat), 7.22−7.33 (m, 3 H,
7.00−7.11 (m, 2 H, Haromat), 7.11−7.21 (m, 4 H, Haromat),
−1
~
7.22−7.37 (m, 5 H, Haromat). IR (film): n = 1694 cm , 1454,
1416, 1289, 1223. MS (CI); m/z (%): 358 (92) [M + H+], 266
(28), 250 (27), 222 (8), 176 (100). C24H23NO2 (357.45).
5.1.9. N-Benzyloxycarbonyl-1-(2,6-dimethylphenyl)-1,2,3,4-
tetrahydroisoquinoline (rac-8c)
According to GP2 from compound 6a (0.495 g, 1.85 mmol)
and 2,6-dimethylphenylMgBr (1.0 M in THF, 5.56 ml,
5.56 mmol). Purification by CC (EtOAc/n-heptane = 10:90).
Yield: 0.452 g (66%); colorless crystals. TLC: Rf = 0.19
~
Haromat), 7.35−7.40 (m, 2 H, Haromat). IR (film): n =
1694 cm−1, 1463, 1410, 1212. MS (CI); m/z (%): 386 (100)
1
(EtOAc/n-heptane = 10:90). M.p. 115 °C. H NMR (d5-nitro-
[M + H+], 294 (15), 280 (34), 91 (10). C26H27NO2 (385.51).
benzene, 140 °C): δ = 2.24 (s, 6 H, 2 CH3), 2.91−3.06 (m, 2 H,
CH2), 3.52 (ddd, J = 13.1, 10.0, 4.5 Hz, 1 H, CH2), 4.56 (dt,
J = 13.1, 4.1 Hz, 1 H, CH2), 5.05 (d, J = 12.4 Hz, 1 H, CH2O),
5.10 (d, J = 12.4 Hz, 1 H, CH2O), 6.35 (s, 1 H, CH), 6.63 (d,
5.1.13. 1-Phenyl-1,2,3,4-tetrahydroisoquinoline (rac-4a)
and 1-phenyl-1,2,3,4-tetrahydroisoquinolinium chloride (rac-
4a·HCl)
According to GP3 from compound rac-8a (1.082 g,
3.15 mmol).
J = 7.9 Hz, 1 H, Haromat), 6.96−7.02 (m, 3 H, Haromat), 7.06
−1
~
−7.32 (m, 8 H, Haromat). IR (KBr): n = 1707 cm , 1399,
1363, 1239. MS (CI); m/z (%): 372 (32) [M + H+], 266 (23),
rac-4a: Yield: 0.602 g (91%); colorless crystals. TLC: Rf
= 0.19 (EtOAc/n-heptane = 20:80 + 2% EtMe2N). M.p. 94 °C
(lit.: 94–96 °C [16]). 1H NMR (CDCl3, 20 °C): δ = 1.91 (br. s,
1 H, NH), 2.80−2.90 (m, 1 H, CH2), 3.01−3.15 (m, 2 H, CH2),
3.25−3.34 (m, 1 H, CH2), 5.12 (s, 1 H, CH), 6.77 (d,
J = 7.8 Hz, 1 H, Haromat), 7.02−7.09 (m, 1 H, Haromat), 7.13
−7.19 (m, 2 H, Har−o1mat), 7.26−7.37 (m, 5 H, Haromat). IR
264 (10), 176 (100). C25H25NO2 (371.48).
5.1.10. N-Benzyloxycarbonyl-8-methyl-1-phenyl-1,2,3,4-
tetrahydroisoquinoline (rac-8d)
According to GP2 from compound 6b (0.399 g, 1.42 mmol)
and PhMgCl (1.8 M in THF, 2.50 ml, 4.26 mmol). Purification
by CC (EtOAc/n-heptane = 10:90). Yield: 0.284 g (56%); col-
orless oil. TLC: Rf = 0.15 (CH2Cl2/n-heptane = 50:50). 1H
NMR (d5-nitrobenzene, 140 °C): δ = 2.04 (s, 3 H, CH3), 2.73
(dt, J = 16.4, 5 Hz, 1 H, CH2), 2.96 (ddd, J = 16.4, 9.8, 6.6 Hz,
1 H, CH2), 3.30 (ddd, J = 13.0, 9.8, 5 Hz, 1 H, CH2), 4.05
(dddd, J = 13.0, 6.6, 5, 0.7 Hz, 1 H, CH2), 5.32 (d,
J = 12.6 Hz, 1 H, CH2O), 5.37 (d, J = 12.6 Hz, 1 H, CH2O),
6.67 (s, 1 H, CH), 7.00 (d, J = 7.4 Hz, 1 H, Haromat), 7.03 (d,
J = 7.4 Hz, 1 H, Haromat), 7.14 (t, J = 7.4 Hz, 1 H, Haromat),
~
(KBr): n = 2922 cm , 1492, 1453. MS (CI); m/z (%): 210
(100) [M + H+], 132 (8). C15H15N (209.29).
rac-4a·HCl: Colorless crystals. M.p. 223 °C (lit.:
227–229 °C [17]). 1H NMR (d4-MeOH, 20 °C): δ = 3.10
−3.38 (m, 2 H, CH2), 3.46−3.61 (m, 2 H, CH2), 5.78 (s, 1 H,
CH), 6.85 (d, J = 7.8 Hz, 1 H, Haromat), 7.19−7.26 (m, 1 H,
H
aromat), 7.33−7.41 (m, 2 H, Haromat), 7.48−7.53 (m, 5 H,
−1
~
H
aromat). IR (KBr): n = 2888 cm , 2754, 2620, 2537, 1577,
1496, 1453. MS (CI); m/z (%): 210 (100) [M – HCl + H+],
7.19−7.29 (m, 6 H, Haromat), 7.30−7.36 (m, 2 H, Haromat),
132 (4). C15H16ClN (245.75).
−1
~
7.43−7.47 (m, 2 H, Haromat). IR (film): n = 1694 cm , 1426,
1319, 1201. MS (CI); m/z (%): 358 (100) [M + H+], 280 (11),
5.1.14. 1-(2-Methylphenyl)-1,2,3,4-tetrahydroisoquinoline
(rac-4b) and 1-(2-methylphenyl)-1,2,3,4-
266 (25), 222 (17). C24H23NO2 (357.45).
tetrahydroisoquinolinium hydrochloride (rac-4b·HCl)
According to GP3 from compound rac-8b (107 mg,
0.30 mmol).
5.1.11. N-Benzyloxycarbonyl-8-methyl-1-(2-methylphenyl)-
1,2,3,4-tetrahydroisoquinoline (rac-8e)
According to GP2 from compound 6b (0.469 g, 1.67 mmol)
rac-4b: Yield: 53 mg (79%); colorless oil. TLC: Rf = 0.29
(EtOAc/n-heptane = 20:80 + 2% EtMe2N). H NMR (CDCl3,
1
and (2-methylphenyl)MgBr (1.0
M
in THF, 5.00 ml,
5.00 mmol). Purification by CC (CH2Cl2/n-heptane = 80:20).
20 °C): δ = 1.75 (br. s, 1 H, NH), 2.42 (s, 3 H, CH3), 2.80

M. Ludwig et al. / European Journal of Medicinal Chemistry 41 (2006) 1003–1010
1009
−1
~
−2.88 (m, 1 H, CH2), 3.02−3.16 (m, 2 H, CH2), 3.28−3.35 (m,
1 H, CH2), 5.35 (s, 1 H, CH), 6.70 (d, J = 7.7 Hz, 1 H,
Haromat). IR (KBr): n = 3448 cm , 2920, 2696, 2633, 1577,
1473, 1452. MS (CI); m/z (%): 224 (100) [M – HCl + H+],
146 (6). C16H18ClN (259.78).
H
aromat), 7.00−7.08 (m, 2 H, Haromat), 7.10−7.23 (m, 5 H,
−1
~
Haromat). IR (Film): n = 1491 cm , 1453. MS (CI); m/z (%):
224 (100) [M + H+], 132 (17). C16H17N (223.32).
5.1.17. 8-Methyl-1-(2-methylphenyl-1,2,3,4-
tetrahydroisoquinoline (rac-4e HCl)
1
rac-4b·HCl: Colorless crystals. M.p. 123 °C. H NMR (d4-
MeOH, 20 °C): δ = 2.55 (s, 3 H, CH3), 3.21 (dt, J = 17.5,
5.3 Hz, 1 H, CH2), 3.37 (dd, J = 17.5, 7.5 Hz, 1 H, CH2),
3.56−3.64 (m, 2 H, CH2), 6.01 (s, 1 H, CH), 6.74 (d,
According to GP3 from compound rac-8e (0.449 g,
1.21 mmol). Purification by CC (EtOAc/n-heptane = 20:80
+ 2% EtMe2N). TLC: Rf = 0.26 (EtOAc/n-heptane = 20:80
+ 2% EtMe2N).
J = 7.9 Hz, 1 H, Haromat), 7.05 (d, J = 7.8 Hz, 1 H, Haromat),
−1
~
7.17−7.42 (m, 6 H, Haromat). IR (KBr): n = 3423 cm , 2920,
rac-4e·HCl: Yield: 152 mg (46%); colorless crystals. M.p.
260 °C. H NMR (d4-MeOH, 20 °C): δ = 1.86 (s, 3 H, CH3),
2754, 1584, 1494, 1456, 1420. MS (CI); m/z (%): 224 (100)
1
[M – HCl + H+], 132 (8). C16H18ClN (259.78).
2.65 (s, 3 H, CH3), 3.18−3.30 (m, 2 H, CH2), 3.37−3.43 (m, 2
H, CH2), 5.99 (s, 1 H, CH), 6.76 (dd, J = 7.8, 1.0 Hz, 1 H,
5.1.15. (2,6-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline
(rac-4c) and (2,6-dimethylphenyl)-1,2,3,4-
tetrahydroisoquinolinium chloride (rac-4c·HCl)
According to GP3 from compound rac-8c (163 mg,
0.44 mmol).
rac-4c: Yield: 80 mg (77%); colorless crystals. TLC: Rf
= 0.40 (EtOAc/n-heptane = 20:80 + 2% EtMe2N). M.p. 70 °C.
1H NMR (CDCl3, 20 °C): δ = 1.75 (br. s, 1 H, NH), 1.99 (s, 3
H, CH3), 2.52 (s, 3 H, CH3), 2.75−2.85 (m, 1 H, CH2), 3.11
−3.23 (m, 2 H, CH2), 3.39−3.48 (m, 1 H, CH2), 5.62 (s, 1 H,
CH), 6.63 (d, J = 7.8 Hz, 1 H, Haromat), 6.95−7.04 (m, 2 H,
H
aromat), 7.11 (br. d, J = 7.4 Hz, 1 H, Haromat), 7.18 (td,
J = 7.5, 1.2 Hz, 1 H, Haromat), 7.23 (d, J = 7.7 Hz, 1 H,
aromat), 7.29 (d, J = 7.6 Hz, 1 H, Haromat), 7.36 (td, J = 7.5,
1.3 Hz, 1 H, Haromat), 7.42 (br. d, J = 7.5 Hz, 1 H, Haromat).
H
−1
~
IR (KBr): n = 2917 cm , 2724, 1581, 1472, 1433. MS (CI);
m/z (%): 238 (100) [M – HCl + H+], 146 (9). C17H20ClN
(273.81).
5.1.18. 8-Methyl-1-(2,6-dimethylphenyl)-1,2,3,4-
tetrahydroisoquinolinium chloride (rac-4f·HCl)
~
aromat), 7.05−7.15 (m, 4 H, Haromat). IR (KBr): n =
H
2919 cm−1, 2771, 1586, 1455. MS (CI); m/z (%): 238 (100)
According to GP3 from compound rac-8f (0.643 g,
1.67 mmol).
[M – HCl + H+], 132 (20). C17H19N (237.34).
1
rac-4c·HCl: Colorless crystals. M.p. 275 °C. H NMR (d4-
rac-4f·HCl: Yield: 409 mg (85%); colorless crystals. M.p.
> 300 °C. TLC: Rf = 0.45 (EtOAc/n-heptane = 20:80 + 2%
EtMe2N). 1H NMR (d4-MeOH, 20 °C): δ = 1.68 (s, 3 H,
CH3), 1.74 (s, 3 H, CH3), 2.67 (s, 3 H, CH3), 3.17 (dt,
J = 17.4, 4.0 Hz, 1 H, CH2), 3.24−3.34 (m, 1 H, CH2), 3.50
(ddd, J = 12.3, 10.7, 4.3 Hz, 1 H, CH2), 3.58 (ddd, J = 12.3,
5.2, 4 Hz, 1 H, CH2), 6.19 (s, 1 H, CH), 7.01–7.05 (1 M, 1 H,
MeOH, 20 °C): δ = 1.84 (s, 3 H, CH3), 2.61 (s, 3 H, CH3), 3.19
(dt, J = 17.4, 3.1 Hz, 1 H, CH2), 3.26−3.41 (m, 1 H, CH2),
3.65−3.75 (m, 2 H, CH2), 6.23 (s, 1 H, CH), 6.72 (d,
J = 8.0 Hz, 1 H, Haromat), 7.11 (d, J = 7.1 Hz, 1 H, Haromat),
7.17−7.22 (m, 1 H, Haromat), 7.24−7.35 (m, 4 H, Haromat). IR
−1
~
(KBr): n = 2919 cm , 2771, 1586, 1455. MS (CI); m/z (%):
238 (100) [M – HCl + H+], 132 (20). C17H20ClN (273.81).
Haromat), 7.07 (d, J = 7.7 Hz, 1 H, Haromat), 7.16 (d, J = 7.6 Hz,
1 H, Haromat), 7.23 (d, J = 7.4 Hz, 1 H, Haromat), 7.24−7.27 (m,
−1
5.1.16. 8-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (rac-
4d) and 8-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolinium
chloride (rac-4d·HCl)
According to GP3 from compound rac-8d (195 mg,
0.55 mmol). Purification by CC (EtOAc/n-heptane = 20:80
+ 2% EtMe2N).
~
2 H, Haromat). IR (KBr): n = 2968 cm , 2771, 2655, 2478,
1581, 1466, 1444, 1428. MS (CI); m/z (%): 252 (100) [M –
HCl + H+], 146 (18). C18H22ClN (287.83).
5.1.19. Radioreceptor assay
rac-4d: Yield: 74 mg (61%); colorless crystals. TLC: Rf
= 0.19 (EtOAc/n-heptane = 20:80 + 2% EtMe2N). M.p. 79 °C.
1H NMR (CDCl3, 20 °C): δ = 1.85 (br. s, 1 H, NH), 1.89 (s, 3
H, CH3), 2.74−2.84 (m, 2 H, CH2), 2.84−3.04 (m, 2 H, CH2),
5.19 (s, 1 H, CH), 6.97 (d, J = 7.3 Hz, 1 H, Haromat), 7.06 (d,
J = 7.6 Hz, 1 H, Haromat), 7.07−7.12 (m, 2 H, Haromat), 7.14 (t,
The binding assay was performed as described previously in
[18]. Ki values for test compounds were calculated from com-
petition experiments with at least six concentrations of test
compounds, by the use of InPlot 4.0 (GraphPad Software,
San Diego, CA). Data are expressed as mean standard error
of the means (S.E.M.) of three experiments, each carried out in
triplicate.
J = 7.5 Hz, 1 H, Haromat), 7.21−7.32 (m, 3 H, Haromat). IR
−1
~
(KBr): n = 1459 cm , 1448, 1257, 1028. MS (CI); m/z (%):
224 (100) [M + H+], 194 (39), 146 (9). C16H17N (223.32).
Acknowledgements
1
rac-4d·HCl: Colorless crystals. M.p. 233 °C. H NMR (d4-
MeOH, 20 °C): δ = 1.93 (s, 3 H, CH3), 3.12−3.38 (m, 4 H,
CH2CH2), 5.91 (s, 1 H, CH), 7.13 (d, J = 7.3 Hz, 1 H,
Haromat), 7.23 (d, J = 7.6 Hz, 1 H, Haromat), 7.25−7.29 (m, 2 H,
Financial support of this work by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie and the
BMBF is gratefully acknowledged.
H
aromat), 7.31 (t, J = 7.5 Hz, 1 H, Haromat), 7.43−7.49 (m, 3 H,

1010
M. Ludwig et al. / European Journal of Medicinal Chemistry 41 (2006) 1003–1010
[8] K.T. Wanner, H. Beer, G. Höfner, M. Ludwig, Eur. J. Org. Chem. 9
References
(1998) 2019.
[9] (a) H.J. Sheriffs, K. Shirakawa, J.S. Kelly, H.J. Overman, A. Kuno, M.
Okubo, S.P. Butcher, Eur. J. Pharmacol. 247 (1993) 319. (b) H. Takasu-
gi, A. Kuno, M. Ohkubo, EP0336228A1 (1998). (c) K. Katsuta, H. Na-
kanishi, K. Shirakawa, K. Yoshida, K. Takagi, A.J. Tamura, Cereb.
Blood Flow Metab. 15 (1995) 345.
[1] (a) W. Danysz, W. Zajaczkowski, C.G. Parsons, Behavourial. Pharmacol.
6 (1995), 455. (b) G. Dannhardt, B.K. Kohl, Curr. Med. Chem. 5 (1998),
253. (c) Y. Yoneda, K. Ogita, Neurosci. Res. 10 (1991) 1. (d) C.J. Car-
ter, K.G. Lloyd, B. Zivkovic, B.J. Scatton, Pharmacol. Exp. Ther. 253
(1990) 475. (e) I.J. Reynolds, R.J. Miller, Mol. Pharmacol. 33, (1988)
581. (f) K. Yamada, T. Nabeshima, Drug News Perspect. 17 (2004)
435. (g) T.V. Bliss, G.L, Collingridge, Nature 361 (1993) 31.
[2] (a) S.M. Rothman, J.W. Olney, Trends Neurosci. 10 (1987) 299. (b) S.H.
Graham, K. Shiraishi, S.S. Panter, R.P. Simon, A.I. Faden, Neurosci.
Lett. 110 (1990) 124. (c) B.S. Meldrum, Cerebrovasc. Brain Metab.
Rev. 2 (1990) 27. (d) P.D. Leeson, L.L. Iversen, J. Med. Chem. 37
(1994) 4053. (e) W. Danysz, C.G. Parsons, I. Bresink, G. Quack,
DN&P 8 (1995) 261.
[3] A.B. Petrenko, T. Yamakura, H. Baba, K. Shimoji, Anesth. Analg. 97
(2003) 1108.
[4] (a) D.J. Hewitt, Clin. J. Pain. 16 (2 Suppl.) (2000) S73. (b) K. Raith, G.
Hochhaus, Int. J. Clin. Pharmacol. Ther. 42 (2004) 191.
[5] T.A. Simeone, R.M. Sanchez, J.M. Rho, J. Child Neurol. 19 (2004) 343.
[6] (a) N.A. Anis, S.C. Berry, N.R. Burton, D. Lodge, Brit. J. Pharmac. 79
(1983) 565. (b) S.C. Berry, N.A. Anis, D. Lodge, Brain Res. 307 (1984)
85.
[10] F. Johnson, Chem. Rev. 68 (1968) 375.
[11] P.S. Charifson, J.P. Bowen, S.D. Wyrick, A.J. Hoffman, M. Corey, A.D.
McPhail, R.B. Mailman, J. Med. Chem. 32 (1989) 2050.
[12] M. Ludwig, K. Polborn, K.T. Wanner, Heterocycles 61 (2003) 299.
[13] (a) K.T. Wanner, A. Kärtner, Heterocycles 26 (1987) 921. (b) H. Wald-
mann, G. Schmidt, H. Henke, M. Burkard, Angew. Chem. 107 (1995)
2608. (c) K. Hashigaki, K. Kan, N. Qais, Y. Takeuchi, M. Yamato,
Chem. Pharm. Bull. 39 (1991) 1126. (d) D.L. Comins, M.M. Badawi,
Heterocycles 32 (1991) 1869. (e) G. Gossmann, D. Guillaume, H.-P.
Husson, Tetrahedron Lett. 37 (1996) 4369. (d) A.I. Meyers, Tetrahedron
48 (1992) 2589. (e) W.N. Speckamp, M.J. Moolenaar, Tetrahedron 56
(2000) 3817.
[14] D.M. Bailey, C.G. DeGrazia, J. Med. Chem. 16 (1973) 151.
[15] K.T. Wanner, I. Praschak, U. Nagel, Arch. Pharm. (Weinheim) (1990)
335.
[16] H. McNab, L.C. Monahan, J. Chem, Soc. Perkin Trans I (1988) 869.
[17] S.J. Brodrick, Chem. Soc. (1949) 2587.
[7] N.M. Gray, B.K. Cheng, S.J. Mick, C.M. Lair, P.C. Contreras, J. Med.
Chem. 32 (1989) 1242.
[18] G. Höfner, K.T. Wanner, J. Recept. Signal Transduct. Res. 16 (1996)
297.