Synthesis and dopamine receptor pharmacological evaluations on ring C ortho halogenated 1-phenylbenzazepines

Article abstract of DOI:10.1016/j.bmcl.2020.127305

A series of 1-phenylbenzazepines containing bromine or chlorine substituents at the ortho position of the appended phenyl ring (2′-monosubstituted or 2′,6′- disubstituted patterns) were synthesized and evaluated for affinity towards dopamine D₁

Full text of DOI:10.1016/j.bmcl.2020.127305

Bioorganic & Medicinal Chemistry Letters 30 (2020) 127305
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and dopamine receptor pharmacological evaluations on ring C
ortho halogenated 1-phenylbenzazepines
a,b
a
a
c
a,b,d,⁎
Rajan Giri , Hari K. Namballa , Ananta Sarker , Ian Alberts , Wayne W. Harding
a
b
c
Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA
th
Program in Chemistry, CUNY Graduate Center, 365 5 Avenue, New York, NY 10016, USA
LaGuardia Community College, Department of Chemistry, 31-10 Thompson Avenue, LIC, NY 11104, USA
Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA
d
A R T I C L E I N F O
A B S T R A C T
Keywords:
Dopamine
D1
A series of 1-phenylbenzazepines containing bromine or chlorine substituents at the ortho position of the ap-
pended phenyl ring (2′-monosubstituted or 2′,6′- disubstituted patterns) were synthesized and evaluated for
affinity towards dopamine D
1
R, D
2
R and D R. As is typical of the 1-phenylbenzazepine scaffold, the compounds
5
D5
displayed selectivity towards D
1
R and D
5
R; analogs generally lacked affinity for D R. Interestingly, 2′,6′-dichloro
2
D2
substituted analogs showed modest D
5
R versus D R selectivity whereas this selectivity was reversed in com-
1
Benzazepine
pounds with a 2′-halo substitution pattern. Compound 10a was identified as a D
1
R antagonist (K = 14 nM;
i
IC50 = 9.4 nM).
The neurotransmitter dopamine is implicated in a number of phy-
siological functions in both the periphery and central nervous system
activity (i.e. full agonists, partial agonists, antagonists) have been
18–23
identified with this scaffold.
used as research tools in pharmacological studies. For example, SCH
23,390 (1, Fig. 1) is a widely used D R-like antagonist tool; it displays
very high affinity for D R and D R (0.2 and 0.3 nM respectively). SKF
38,393 (2) is a widely used D R-like agonist with strong affinity for D
and D R (1.0 and 0.5 nM respectively). Fenoldopam (3), a periph-
erally restricted D R-like partial agonist is currently the only compound
from this class that is in use clinically (it is used as a fast-acting anti-
A number of these compounds are
(
CNS) such as locomotion, blood pressure regulation, cognition and
1–7
emotion.
Perturbations in dopaminergic neurotransmission underlie
1
2
4
some CNS disorders such as Parkinson’s disease, schizophrenia and
1
5
8
–11
drug abuse.
Therefore normalization of dopaminergic neuro-
1
1
R
2
5
transmission with pharmacological agents has been explored as a means
to treat these conditions.
5
1
Dopamine exerts its pharmacological actions via agonist activity at
2
6
5
dopamine receptors (D
1
R – D
and D
-like” (comprising D R, D
and function of the receptors and pharmacological studies.
discovery of ligands that are highly selective for either the D
sub-types has proved challenging due to the close transmembrane
structural similarity between D R and D R (> 80% homology in
transmembrane regions). Thus, commercially available D R ligands (i.e.
R-like” ligands) usually display similar affinity at D R. It is only
quite recently that D R subtype selective ligands have been dis-
The availability of highly selective ligands for either D R or
R is of current interest as such compounds would be useful tools to
5
R). Dopamine receptors are classified as
hypertensive drug).
There have been several structure-activity relationship (SAR) stu-
dies on 1-phenylbenzazepines as D R-like receptor ligands and these
studies have established that the aryl substituent groups as well as the
nitrogen substituent can significantly impact D R-like affinity, D R-like
“
D
1
-like” (constituted by D
1
5
receptor sub-types – D
1
R and D
5
R)
and “D
2
2
3
R and D R) based on the structure
4
1
1
2–15
The
1
R or D
5
R
1
1
2
7–32
selectivity versus “D -like” receptors as well as functional activity.
2
1
5
Although several SAR studies have been performed on the scaffold, it
has not been determined how halogen substituents in the ortho position
of ring C in the 1-phenylbenzazepine framework impacts affinity and
selectivity for dopamine receptors; there is no data available concerning
1
5
“D
1
1
1
6,17
closed.
1
the D
1
R versus D R affinity of the compounds. Given this gap in the SAR
5
D
5
of 1-phenylbenzazepines, we set out to examine the role of ring C ortho
unravel the individual roles of D
1
R and D
5
R in various physiological
halo substituents on D
1
R/D R affinity in this scaffold. We hypothesized
5
processes and serve as lead molecules for related CNS disorders.
The 1-phenylbenzazepine framework is a classical template for D
that such substituents might cause differences in receptor interactions
with the substituents themselves and/or lead to modified conformations
1
R-
like ligands and numerous compounds along a continuum of functional
of the molecule as a whole that could directly influence D
1
R and D R
5
⁎
Corresponding author at: Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA.
E-mail address: whardi@hunter.cuny.edu (W.W. Harding).
https://doi.org/10.1016/j.bmcl.2020.127305
Received 29 April 2020; Received in revised form 27 May 2020; Accepted 1 June 2020
Available online 04 June 2020
0960-894X/ © 2020 Elsevier Ltd. All rights reserved.

R. Giri, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127305
Acid-catalyzed cyclization of 5 afforded the benzazepine framework of
compounds 6a-d. Compounds 6a-d served as key intermediates from
which the synthesis diverged to prepare other analogs with variations
in the phenolic moiety and/or N-substituent.
Thus, treatment of compounds 6b with BBr gave the catecholic
3
compound 7. The secondary amine in compounds 6b-d was methylated
via reductive amination to give analogs 10a-c respectively. Treatment
of compounds 6b-d with allyl bromide allowed for the preparation of N-
allylated analogs 11a-c. Compounds 10c and 11c in turn were de-
Fig. 1. Structures of typical 1-phenylbenzazepine
D
1
R-like ligands
–
methylated by reaction with BBr
spectively.
3
affording catechols 12 and 13 re-
Fenoldopam, SCH 23,390 and SKF 38393.
The binding affinity of compounds 6a-d, 7, 10a-c, 11a-c, 12 and 13
were assessed at dopamine D
1
, D
2
and D
5
receptors. Data for these as-
affinity and selectivity. Thus, we set out to synthesize a set of 1-phe-
nylbenzazepine derivatives with variations in the ring A moiety (either
a catechol or protected catechol motif), nitrogen alkyl group substituent
and ring C ortho halogenated motif.
sessments are presented in Table 1 as K
i
values in nM. Compounds 6a-d
had D
1
R affinities ranging from 72 to 147 nM. Affinities at D R for this
5
sub-group of compounds were slightly lower overall (ranging from 82
to 483 nM), so that on a whole, compounds 6a-d were slightly more
The analogs were synthesized as shown in Scheme 1. The epoxides 9
were available commercially or could be readily synthesized from the
corresponding styrenes 8. We initially attempted reaction of amine 4
and epoxides 9 to form amino alcohols 5 without the use of any ad-
ditives/catalysts, as is typically done for the synthesis of 1-phe-
selective for D
1
R over D R. Compound 6c is interesting as it is the only
5
compound of the 6a-d subset that was D
5
R selective over D
1
R (3-fold).
Compounds 6a, 6b and 6d displayed modest selectivity for D
1
R over
D
5
R (up to 3-fold).
3
3–35
Compound 7 with a bromo substituent, showed strong D
1
R and D R
5
nylbenzazepine syntheses,
but found the reactions to be low
affinity. In comparing phenol 7 to its C7 methoxy analog 6d, it is ap-
yielding. Presumably this less than favorable outcome was due to the
steric hindrance in the epoxides used. Lewis acids or lithium salts have
often been used to promote ring opening of epoxides with amine nu-
parent that the effect of cleavage of the C7 methoxy group to give the
catechol 7, results in a roughly 3-fold increase in D R affinity; im-
1
3
6–38
provement in affinity at D
Compounds 10a-c are the N-methylated analogs of 6b-d respec-
tively; compounds 10a-c as a group displayed stronger D R affinity
5
R was more modest.
cleophiles.
As LiNTf was reported to provide high yields in such
2
3
9
reactions, we examined the use of this reagent and were happy to find
1
that the reactions of 4 and 9 to form 5 proceeded in reasonable yield.
Scheme 1. Reagents and Conditions: (a) 1. mCPBA, DCM, rt, 12 h; 2. NaOH, rt, (88–96%); (b) 9, LiNTf
2
, THF, reflux, 24 h, (56–76)%; (c) 1. TFA, H
2
SO , rt, 5 h; 2.
4
NaOAc, (43–54%); (d) BBr
3
, DCM, 0 °C, 4 h, (56–80%); (e) HCHO, Na(OAc)
3
BH, ACN, rt, 12 h, (23–48%); (f) Allyl Bromide, TEA, ACN, rt, 16 h, (56–64%).
2

R. Giri, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127305
Table 1
Binding affinity of analogs at D
1
R, D
2
R and D R.
5
Cmpd #
R
R
1
X
X
1
K
i
(nM)a.
D1b
D2c
D5d
e
6
6
6
6
7
1
1
1
1
1
1
1
1
a
b
c
Me
Me
Me
Me
H
H
H
H
Cl
H
H
H
Cl
H
H
Cl
H
H
H
H
126.4 ± 9.1
147.4 ± 4.1
76.1 ± 3.6
72 ± 5.6
na
309.9 ± 23
482.8 ± 29.4
25.4 ± 2.6
82 ± 6.2
H
Cl
Cl
Br
Br
Cl
Cl
Br
Cl
Cl
Br
Br
Br
na
H
na
d
H
na
H
26 ± 3.1
na
67 ± 7.1
0a
0b
0c
1a
1b
1c
2
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Allyl
Allyl
Allyl
Me
Allyl
14 ± 2.3
na
46.4 ± 3.8
49.1 ± 3.7
47 ± 3.2
144.6 ± 9.0
16 ± 1.4
na
na
48.3 ± 8.2
1044 ± 59.2
41 ± 2.8
na
264.4 ± 13.6
479.1 ± 39.2
501 ± 64
1507.8 ± 89.2
na
na
na
59.4 ± 4.9
132.9 ± 8.9
4.04 ± 0.2
223.2 ± 18.6
442.2 ± 56
3
H
(
+)-Butaclamol
Haloperidol
SKF 83,566
5.58 ± 0.3
3.95 ± 0.2
e
a
Experiments carried out in triplicate; [3H]SCH23390 used as radioligand; [3H]N-methylspiperone used as radioligand; d[3H]SCH23390 used as radioligand; na –
b
c
not active (< 50% inhibition in a primary assay when tested at 10 µM).
than their N-des-methyl counterparts. Compounds 10a and 10c had the
similar (for 10a/10c) or were worse for the bromo analog (for 11a/
11c). Therefore, it appears that in this series, the presence of an N-alkyl
substituent group does not lead to a strong preference for binding of the
strongest D
1
R affinity of any compound evaluated for this study (K of
i
1
4 and 16 nM for 10a and 10c respectively). The compounds in this
sub-group with mono-halogen substituents (10a and 10c) showed
monobromo versus monochloro variants at D R; however, the absence
1
modest D
1
R selectivity over D
5
R (3-fold and 4-fold respectively), but
of an N-alkyl substituent leads to stronger binding of the monobromo
versus monochloro congeners at D R.
We selected the compound with the highest D
for further evaluation of functional activity. Thus, compound 10a was
this selectivity was reversed in the dichloro substituted compound 10b.
Similar trends as for the N-methylated analogs 10a-c were seen for
the N-allylated analogs 11a-c. In that regard, both the mono-halo
1
1
-like receptor affinity
R assays that mea-
substituted analogs 11a and 11c were D
1
R selective whereas the di-
evaluated for agonist and antagonist activity in D
1
chloro substituted analog was D
5
R selective. In general, the N-allyl
sured cAMP modulation by Eurofins Lead Hunter Discovery Services. As
expected, (based on structural similarity to 3) 10a displayed strong
antagonist activity in these assays (IC50 = 9.4 nM for 10a; IC50 of
positive control SCH 39166 = 1.5 nM). No agonist activity was de-
tected for 10a.
analogs displayed lower affinity for D
1
R and D R than their N-methyl
5
congeners.
The catecholic analogs 12 and 13 are the O-demethylated analogs of
1
0c and 11c respectively; both 12 and 13 showed lower D
1
R and D
5
1
R
R
affinity than their methylated precursors and both also had modest D
In order to provide insights into the important receptor-ligand in-
teractions between the ortho halogen substituted 1-phenylbenzapines
selectivity versus D R (in the 3- to 4-fold range).
5
In analysis of the effect of monohalogenated versus dihalogenated
substitutions in the pendant aryl ring, interesting observations emerge.
In the case of the 6b/6c pair, the dihalogenated compound 6c showed
and the D
1
R and D R, computational docking studies were conducted
5
for the series of analogs in Table 1. In this context, we explored the
docked ligand poses and identified key interactions that have a sig-
nificant impact on binding to the dopamine receptors for this ligand
series. These efforts focused mainly on the compounds 7, 10a and 10c,
higher D
1
R and D R affinities than the monohalogenated congener 6b.
5
However, a similar change in the 10a/10b pair and the 11a/11b pair
resulted in diminished D
1
R and D
5
R affinities for the corresponding
which displayed the best experimental binding affinities to D
1
R.
R were generated and utilized in
R homology model was constructed from
dihalogenated analogs. This result indicates that the presence of an N-
Homology models of D
1
1
R and D
5
alkyl substituent is more favorable for binding of the monohalogenated
the docking studies. The D
versus their dihalogenated congeners at D
1
R/D
5
R, whereas absence of
the high-resolution crystal structure of the human β -adrenergic G
2
such a substituent leads to a stronger preference towards binding of the
dihalogenated versus monohalogenated variants.
protein-coupled receptor (GPCR) with pdb code 2RH1 followed by in-
duced fit docking with several halogenated 1-phenylbenzazepine ana-
4
0
Comparison of data for the 6b/6d, 10a/10c and 11a/11c com-
pound pairs enabled an analysis of the effect of monochloro versus
monobromo substitution in the analog series. In the case of the 6b/6d
logs. In a similar manner, the D R homology model was created from
5
the high-resolution crystal structure of the β -adrenergic GPCR with
1
pdb code 6H7J followed by induced fit docking with the benzazepine
4
1
pair, the bromo analog 6d had higher D
1
R and D
5
R affinity than the
analogs. Models of appropriate amino acid backbone and side-chain
orientations in the ligand binding site. The homology model building
procedure involved application of the Schrödinger Prime Structure
Prediction, Induced Fit Docking and Glide software tools in conjunction
with manual intervention to support the formation of known key re-
ceptor-ligand interactions. The docking runs of the 1-phenylbenzaze-
chloro analog 6b. However, in the case of the 10a/10c and 11a/11c
pairs, changing from a chloro group to a bromo group did not result in a
similar increase in affinity of the brominated analogs for the D R as was
1
seen for 6b/6d; affinities for the chloro and bromo variants were si-
milar (e.g. 14 nM and 16 nM for 10a and 10c respectively at D R).
Meanwhile, at the D R, affinities of the bromo and chloro analogs were
1
5
pine analogs into the
D
1
R
and
D R binding sites utilized the
5
3

R. Giri, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127305
Compounds 10a and 10c form docked poses with binding energies of
−
8.2 kcal/mol and −8.1 kcal/mol, respectively, which are very similar
to those in the D R binding pocket.
1
Overall, the computationally predicted binding energies for the
docked series of halogen substituted 1-phenylbenzapine derivatives in
Table 1 are similar in both the D
1
R and D R structures or a little better
5
in D R as a consequence of the slightly stronger hydrogen bonding and
5
π-π hydrophobic interactions. In this context, the docking scores do not
align with the selectivity trends derived from the experimental binding
affinities. This is at least partially attributable to the modest nature of
the observed D
1
R/D R experimental selectivities of the ring C haloge-
5
nated analogs. Furthermore, D
1
R and D R are very similar structurally
5
in the ligand binding pocket, which provides justification for the close
computational binding energies for most of the compounds in these two
target sites. The docking outcomes for the compounds in Table 1 in-
volved the R enantiomers whereas the affinity data were obtained with
racemic mixtures and this could also have an impact on the match
between the experimental and computational results. Docking simula-
tions were investigated with the S enantiomers, however, they gener-
ated similar trends compared to the R enantiomers with, in general,
slightly worse predicted binding energies in both the D
targets.
1
R and D R
5
In conclusion, this study extends the available SAR information on
1
-phenylbenzazepines as D
ring C ortho halogen substituents. As is evident from examination of the
data, the compounds in this study maintain selectivity for D -like re-
ceptors over D R, with modest selectivity for either D R or D R. As
compared to known 1-phenylbenzapeine D R-like tools such as 1 and 2,
it is apparent that the ortho halogen group does not significantly im-
prove D R or D R affinity. However, one of the findings from this work
is that compounds with di-ortho-halo substituents (i.e. C2′/C6′ sub-
stitution) favor binding to D R, whereas compounds with a mono-ortho-
halo (C2′) substituent favor D R binding over D R. In addition, the SAR
data suggests that the most favorable outcome for good D R affinity is
1
R-like ligands with regards to the effect of
1
2
1
5
1
1
5
5
1
5
1
to have either mono-ortho-halogenation in tandem with N-alkyl sub-
stitution or di-ortho-halogenation without N-alkyl substitution.
Evaluation of the functional activity of 10a reaffirms the idea that
an 8-hydroxy-7-methoxy moiety favors antagonist rather than agonist
activity. This result is in line with the generally accepted view that a
catechol motif is required for agonist activity in the 1-phenylbenzaze-
pine scaffold.
Fig. 2. Docked poses of compounds 7 (blue carbon atoms), 10a (green carbon
atoms) and 10c (pink carbon atoms) in A - the D
1
R target and B - the D R target.
5
The receptor targets are depicted by secondary structure elements and grey
carbon atoms for select residues. Key quaternary N – Asp salt bridges are de-
picted by the pink dashed lines, H-bonding interactions by the yellow dashed
lines, aromatic H-bonding by the turquoise dashed lines and π-π stacking by the
blue dashed lines. Docking studies were performed with the R enantiomers.
Our molecular docking studies revealed interactions that were re-
levant for affinity of the molecules at D
1
R and D R, but were unable to
5
resolve interactions necessary for the observed modest D R sub-type
1
selectivity of 7, 10a and 10c. Examination of larger sets of compounds
with ortho halogenated patterns in future, including enantiopure ana-
logs, may provide a larger body of data to aid in the challenging opti-
Schrödinger Glide methodology in Standard Precision (SP) mode. Using
this approach, the Glidescore scoring function provided an estimate of
the ligand binding affinities for the highest ranked poses of the ligand
mization of these ligands towards D
selectivity.
1
R or D R potency and sub-type
5
series in the D
1
R and D R targets. The binding poses for the compounds
5
7
, 10a and 10c (docked as the R enantiomers), which gave the best D R
1
experimental affinities, are depicted in Fig. 2A and 2B.
Declaration of Competing Interest
Compounds 7, 10a and 10c give very similar docked poses in the
D
1
R binding pocket as shown in Fig. 2A with binding energies in the
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
range −7.8 kcal/mol to −8.2 kcal/mol. The docked poses display the
quaternary N - Asp103 salt bridge, H-bonding interactions of the ligand
hydroxyl group to the Asn292 side chain, and for compound 7 with an
additional hydroxyl group in the catechol moiety there is also a H-bond
to the Ser198 sidechain, as well as an aromatic H-bond involving the
pendant phenyl group and Ser188.
Acknowledgments
In the D
5
R binding site, the main receptor-ligand interactions for the
This publication was made possible by Grant Number
1SC1DA049961-01 from the National Institutes of Health (NIH). Its
contents are solely the responsibility of the authors and do not ne-
docked poses of compounds 7, 10a and 10c comprise the quaternary N
-
Asp120 salt bridge, hydrogen bonding interactions of the ligand hy-
droxyl group to the Asn316 or Ser229 sidechain, and again for com-
pound 7 there is another hydrogen bond with its second catechol hy-
droxyl group to Ser233, as well as π-π hydrophobic interactions
involving the ligand aromatic rings with Phe312 and Trp116.
cessarily represent the official views of the NIH or its divisions. K de-
i
terminations, and receptor binding profiles were generously provided
by the National Institute of Mental Health's Psychoactive Drug
Screening Program, Contract
# HHSN-271-2008-00025-C (NIMH
4

R. Giri, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127305
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, USA. For experimental details please
refer to the PDSP website http://pdsp.med.unc.edu/ and click on
improved pharmacokinetics: design, synthesis, and biological evaluation of phenol
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