cis- and trans-N-benzyl-octahydrobenzo[g]quinolines. Adrenergic and dopaminergic activity studies

Article abstract of DOI:10.1016/S0960-894X(01)00076-2

In vitro assays on a series of cis- and trans-octahydrobenzo[g]quinolines indicated an unusual trend of affinities at the dopaminergic receptors and α adrenoceptors. The trans N-benzyl analogues exhibited affinity at the α₂ as well as the D1-like receptors whereas their N-unsubstituted congeners showed a distinct preference for the α₂ adrenoceptor. Enhanced activity for the α₂ receptors was also exhibited by the cis N-benzylated isomers. These observations are interpreted by theoretical calculations.

Full text of DOI:10.1016/S0960-894X(01)00076-2

Bioorganic & Medicinal Chemistry Letters 11 (2001) 883–886
cis- and trans-N-Benzyl-octahydrobenzo[g]quinolines.
Adrenergic and Dopaminergic Activity Studies
Kyriaki Thermos,a George E. Froudakis,b Nikos Tagmatarchisb
and Haralambos E. Katerinopoulosb,*
aLaboratory of Pharmacology, School of Medicine, University of Crete, Heraklion 71 110, Crete, Greece
bDivision of Organic Chemistry, Department of Chemistry, University of Crete, Heraklion 71 409, Crete, Greece
Received 31 October 2000; revised 5 January 2001; accepted 31 January 2001
Abstract—In vitro assays on a series of cis- and trans-octahydrobenzo[g]quinolines indicated an unusual trend of affinities at the
dopaminergic receptors and a adrenoceptors. The trans N-benzyl analogues exhibited affinity at the a2 as well as the D1-like
receptors whereas their N-unsubstituted congeners showed a distinct preference for the a2 adrenoceptor. Enhanced activity for the
a2 receptors was also exhibited by the cis N-benzylated isomers. These observations are interpreted by theoretical calculations.
# 2001 Published by Elsevier Science Ltd.
Introduction
geners reveals an unusual trend of activities. As repor-
ted previously, trans 2a exhibits affinity only for the a2
receptor (IC50=130 nM).1 Its N-benzylated derivative,
trans 1a binds weakly to the D1 receptor (IC50=
1.2 mM), shows moderate affinity for the a1 and strong
affinity for the a2 adrenoceptor as indicated by the
respective IC50 values of 218 and 5.9 nM. The cis 1a
isomer has a pharmacological profile similar to that of
trans 2a: it is dopaminergically inactive and shows
(moderate) affinity for the a2 receptor with an
IC50=214 nM.
We have recently reported the synthesis of a series of
octahydrobenzo[g]quinolines along with the preparation
of their -[f] isomers.1 The synthetic methodology—aiming
at the preparation of a adrenergic and dopaminergic
drugs—involved the reaction of 3-(20-(methoxycarbonyl)-
ethyl)-2-tetralones with benzylamine, followed by LiAlH4
reduction of the intermediate enamide and subsequent
NaBH4 reduction of the enamine double bond (Scheme 1).
This process, although furnishing the trans analogues 1a–b
as the predominant products, allows for the isolation of
small amounts of the minor cis isomers. Initial SAR
studies on octahydrobenzo[g]quinolines focused on the
trans compounds, expected by literature precedents to
be the active isomers.2 However, preliminary evaluation
of the pharmacological profile of 1a indicated that some
activity also rests on the cis isomer. Prompted to evalu-
ate the pattern of activity of the cis congeners we isolated
1b and tested it for a1, a2, D1, and D2 receptor affinity.
The 7-methoxy-substituted analogues exhibit the same
trend of affinities. The secondary amine trans 2b binds
only at the a2 adrenoceptor (IC50=67.5 nM), whereas
introduction of the N-benzyl moiety in trans 1b expands
the affinity of the drug to the D1, a1, and a2 receptors
with a distinct preference to the latter (IC50=6.0 nM).
The cis N-benzyl isomer (cis 1b) is dopaminergically
inactive and exhibits 18 times higher affinity
(IC50=38 nM) for the a2, than that for the a1 receptor
(IC50=667 nM).
Results and Discussion
This reversal of activity of cis and trans octahydro-
benzo[g]quinolines calls for an interpretation that
should be based on the topology of each receptor and
the structural requirements that each analogue may ful-
fill for an efficient ‘docking’ in the receptor sites. Dif-
ferences in the pharmacological profile of the trans 2a–b
and trans 1a–b congeners may be attributed to the
presence of the N-benzyl moiety: the secondary amines are
Binding assay results are presented in Tables 1 and 2.
Comparison of activities of the trans secondary amines
2a and 2b with their N-benzylated cis and trans con-
*Corresponding author Tel.: +30-81-393626; fax: +30-81-393601;
e-mail: kater@chemistry.uch.gr
0960-894X/01/$ - see front matter # 2001 Published by Elsevier Science Ltd.
PII: S0960-894X(01)00076-2

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K. Thermos et al. / Bioorg. Med. Chem. Lett. 11 (2001) 883–886
Scheme 1. Reagents and conditions: (i) (CH3O)2CO, CH3ONa, reflux; (ii) LDA (2 equiv.), allyl bromide, ꢀ78 ꢁC; (iii) LiCl, DMSO, H2O, reflux;
(iv) HOCH2CH2OH, p-TsOH, reflux; (v) disiamyl borane, H2O2, NaOH, 0 ꢁC; (vi) Jones reagent, 0 ꢁC; (vii) CH3OH, H2SO4 (conc.), rt; (viii) BnNH2,
AcOH, reflux; (ix) LiAlH4, rt; (x) NaBH4, rt; (xi) H2, 10%Pd/C, EtOH, rt; (xii) allylbromide; (xiii) Bu3SnH, AIBN; PhCH3, reflux; (xiv) I2; (xv) HBr
48%, reflux.
binding only at the a2 receptor while N-benzylation results
in efficient interaction of trans 1a–b with the D1 and a1
receptors and a 10-fold increase in their a2 affinity. Similar
differences in the profile of the trans 1a–b and cis 1a–b
isomers may be due to conformational changes resulting
from the trans and cis fusion of the B and C rings in each
system. The cis 1a–b isomers are dopaminergically inactive
and exhibit a distinct preference to the a2 adrenoceptor.
nitrogen substituents such as small aliphatic chains with
an optimum interaction with the propyl moiety, (a fact
known as the ‘N-propyl phenomenon’)2,3 although tol-
erance to N-substituents as large as iodopropenyl has
been reported in the literature.1,4 Although the above
results are not decisive, it is tempting to propose that
these ‘lipophilic pockets’ have different orientation in
each receptor. D2 receptors appear intolerant to the
structural systems assayed in this study. As mentioned
before, only the presence of additional receptor binding
moieties, such as the 6-hydroxyl group in compound 3c,
allows for an efficient ‘docking’ into the receptor cavity,
still resulting in moderate D2-activity.1 The D1 receptor
appears tolerant to conformations with only minor
deviations of coplanarity of the B and C rings (com-
pounds trans 1a–b), yet the presence of the benzyl group
appears crucial for the drug’s affinity.
To further elucidate the structural aspects which this
pattern of activities is based on, we performed ab initio
calculations to study the orientation of the functional
groups of the energy-minimized conformers. Results are
depicted in Figures 1 and 2.
With the aromatic moieties of cis and trans 1b super-
imposed, rings B and C of trans 1b are extended at the
same plane of the aromatic ring in contrast to the cis 1b
isomer where the cis fusion of the B and C rings ‘locks’
the system in a conformation significantly deviating
from the desired antiperiplanar conformation of the
phenethylamine moiety,2 thus diminishing dopaminer-
gic activity (Fig. 1). This pattern of activity may also
reveal differences in ‘receptor tolerance’. It has long
been proposed that the presence of ‘lipophilic pockets’ is
a crucial factor for the binding of drugs to dopamine
receptors. These lipophilic cavities may effectively fit
This pharmacological profile could be related to the
activity of dihydrexidine5,6 (Chart 1), a full efficacy D1
agonist structurally similar to our systems: super-
imposition of the aromatic rings in trans 1a and dihy-
drexidine indicates a similar orientation of the aromatic
ring D in dihydrexidine and the N-benzyl substituent in
trans 1a (Fig. 2). It is worth noticing here that the D1
binding compounds have also the highest affinity for the
a2 receptor, an affinity profile we observed in previous
studies.1,7
Table 1. Inhibition of [3H]-spiroperidol and [3H]-SCH-23390 binding
to rat striatal membranesa
Table 2. Inhibition of [3H]-prazosin and [3H]-rauwolscine binding to
rat cortical membranesa
Drug
IC50 (mM)
[3H]-Spiroperidol
[3H]-SCH-23390
Drug
IC50 (nM)
[3H]-Rauwolscine
[3H]-Prazosin
trans 2a
trans-1a
cis-1a
NAb
NA
NA
NA
NA
NA
NA
1.20ꢂ0.70
NA
trans 2a
trans-1a
cis-1a
trans 2b
trans-1b
cis-1b
NAb
130ꢂ61
5.9ꢂ1.9
214ꢂ109
67.5ꢂ3.5
6.0ꢂ1.8
38ꢂ24
trans 2b
trans-1b
cis-1b
NA
0.45ꢂ0.21
218ꢂ110
739ꢂ260
2.200ꢂ700
588ꢂ115
667ꢂ177
1500c
NA
—
(ꢂ) ADTNc
0.70ꢂ0.02
(ꢀ) APOd
0.22ꢂ0.05
0.43ꢂ0.05
Noradrenaline
750c
aExperiments were performed 2–4 times in duplicate.
bNot active up to a concentration of 5 mM.
c5,6-Dihydroxy-2-aminotetralin.
aExperiments were performed 2–4 times in duplicate.
bNot active up to a concentration of 5 mM.
cValues from ref 18.
dApomorphine.

K. Thermos et al. / Bioorg. Med. Chem. Lett. 11 (2001) 883–886
885
The dependence of the receptor binding properties of
octahydrobenzoquinolines on the cis/trans fusion of
their ring system has been considered before. According
to a D2 receptor model described by Teeter et al.8 the cis
and trans N-phenethyl analogues of octahydrobenzo-
[f]quinolines must adopt different orientations relative to
the receptor’s transmembrane helices in order to effi-
ciently bind onto the D2 site. These tricyclic octahydro-
benzoquinoline systems are considered ‘good measuring
sticks’ for the evaluation of an ‘ancillary pocket’ fitting
the nitrogen substituent. The a2 affinity observed in
both cis and trans systems is in agreement with earlier
observations on benzo[f]quinoline SAR studies, leading
to the suggestion that ‘the spatial orientation of the
terminal nitrogen relative to the benzene ring is not as
crucial for the a2 adrenoceptor activity’ as it is for the
dopaminergic system in study.9
Apparently, one cannot draw any conclusions from
these studies regarding the function of the drugs as
agonists or antagonists. Radioligand binding assays and
the affinities of drugs for a specific receptor cannot be
used as an index of the drug’s activity. DA-agonist
activity has been reported for a number of trans octa-
hydrobenzo[g]quinolines with at least one hydroxy or
methoxy substituent at the 6-position; N-propyl sub-
stitution though, was consistently necessary for opti-
mal activity.15ꢀ17 Similarly, a2-agonist activity was
reported for 6,7-dihydroxy congeners, the N-propyl
analogue being the one most potent. The affinity of the
trans 1b analogue for both D1 and a1/a2 receptors
might be related to an agonist profile, however func-
tional studies are essential to assess the potential of this
compound.
In conclusion, the results of our study provide addi-
tional information on the dopaminergic receptor and
adrenoceptor topology, contributing to the ongoing
efforts for the strategic planning of drug design.
Chart 1. Dihydrexidine.
Theoretical Treatment
In order to find out the bonding properties and the
orientation of the functional groups of these structures
we performed ab-initio geometry optimizations. All the
calculations were performed with the GAUSSIAN 94
program package.10 The first principle treatment of the
structures presented here involves Density Functional
Theory (DFT) calculations with the three-parameter
hybrid functional of Becke11 using the Lee–Yang–Parr
correlation functional,12 (B3LYP). The atomic basis
set that we used, LANL2DZ, developed by Hay and
Wadt,10 includes relativistic effective core potentials for
heavy atoms (like iodine) and is of double zeta quality.
The ab-initio treatment of such large systems is com-
putationally expensive, but produces results free of
parameters and more accurate than molecular mechanic
calculations, commonly used for this type of systems.13
The method that we use here, DFT/B3LYP, has also
proved to be very accurate for small organic mole-
cules.14 All the geometries presented in this work are
fully optimized with this method.
Figure 1. With the aromatic rings of cis- and trans-1b superimposed,
the trans compound extends to an antiperiplanar conformation of the
phenethylamine moiety, whereas the cis congener adopts an angular
geometry. The distance between the nitrogen atoms in the two isomers
is 2.636 A.
Pharmacology
The pharmacological behavior of the octahydro-
benzo[g]quinoline derivatives was examined with radio-
ligand binding assays as previously described.18 The
dopaminergic activity of these compounds was studied
by examining their inhibition of the specific binding of
[3H]-spiroperidol and [3H]-SCH23390 to D2 and D1
receptors, respectively, in rat striatal membranes. The
same compounds were also tested for a1 and a2 adre-
nergic activity. [3H]-prazosin and [3H]-rauwolscine were
used to label the a1 and a2 adrenergic receptors in
rat cortical membranes, respectively. Compounds that
Figure 2. Superimposed structures of trans-1a and dihydrexidine. The
nitrogen atoms distance is 0.5 A. Another isoenergetic conformation
of dihydrexidine brings the benzyl groups to a closer proximity; how-
ever the N–N distance increases to 2.0 A. In either case the N-benzyl
moieties extend towards the direction of a possible ‘ancillary pocket’.

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K. Thermos et al. / Bioorg. Med. Chem. Lett. 11 (2001) 883–886
displayed inhibitory constant (IC50) values of more than
5 mM were characterized as inactive.
9. Maixner, W.; Flynn, J. R.; Arneric, S. P.; Cannon, J. G.;
Long, J. P. J. Pharmacol. Exp. Ther. 1983, 224, 352.
10. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill,
P. M. W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.;
Keith, T.; Petersson, G. A.; Montgomery, J. A.; Ragha-
vachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J. V.;
Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.; Nanayak-
kara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen,
W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees, D. J.;
Baker, J.; Stewart, J. P.; Head-Gordon, M.; Gonzalez, C.;
Pople, J. A. Gaussian 94, Revision D.4, Gaussian, Inc.: Pitts-
burgh, PA, 1995.
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