Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D3 receptor ligands with extended functionality for probing the secondary binding pocket

Article abstract of DOI:10.1016/j.bmcl.2018.03.084

A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D₃ receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D₃ receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series.

Full text of DOI:10.1016/j.bmcl.2018.03.084

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D3 receptor
ligands with extended functionality for probing the secondary binding
pocket
⇑
Anahid Omran, Shakiba Eslamimehr, A. Michael Crider, William L. Neumann
Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 220 University Park Drive, Edwardsville, IL 62026, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-buty-
lamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at
human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3-hydrox-
yphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary
binding pocket for enhancing affinity and selectivity for the D3 receptor. The N-alkyl analogues constitute
a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary bind-
ing pocket of the D3 receptor. Enantiomeric 3-(3-hydroxyphenyl)pyrrolidine analogues were also pre-
pared in order to test the chirality preference of the orthosteric binding site for this scaffold.
Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of
the homologous series.
Received 17 January 2018
Revised 14 March 2018
Accepted 29 March 2018
Available online xxxx
Keywords:
Dopamine receptors
Dopamine D3 receptor selectivity
D3 secondary binding pocket
Homologous series
Ó 2018 Elsevier Ltd. All rights reserved.
Structure-activity relationships
Since its discovery and cloning in the early 1990 s, the dopa-
mine D3 receptor (D3R) has emerged as a key target for the devel-
opment of selective dopamine agonists for treating Parkinson’s
disease (PD).1 While dopamine D2 receptor (D2R) stimulation has
long been thought to be necessary for the attenuation of motor
dysfunction in PD, a number of the currently important dopamine
agonists (e.g. pramipexole 1) actually have greater affinity for the
D3R subtype.1b,2 In addition to the relief of PD motor symptoms,
D3R activation is directly associated with downstream
neuroprotective and neurorestorative signaling.3 Accordingly, D3R
selective agonists may also enforce a disease-modifying mode of
action by the partial restoration of the function of the damaged
nigrostriatal neuronal connections in PD. In addition, recent stud-
ies have determined that D3R antagonists and partial agonists
may also be used to treat schizophrenia and substance abuse dis-
orders.4 Thus, the D3R has emerged as a key biological target for
the therapeutic manipulation of a variety of neurological condi-
tions associated with an imbalance in dopamine levels.
ing ligands. 3-(3-Hydroxyphenyl)pyrrolidines were first reported
by Hacksell5 and later investigated by Crider6 as potential alterna-
tives to the well-known 3-(3- hydroxyphenyl)piperidine dopamin-
ergics, such as (S)-3-(1-propylpiperidin-3-yl)phenol (3-PPP) (2).
Elegant studies which characterized the D1R and D2R binding activ-
ity of a number of 3-(3-hydroxyphenyl)piperidine and 3-(3-
hydroxyphenyl)-pyrrolidine derivatives, through in vivo pharma-
cological methods (biochemical, motor function, and behavioral
assays), were reported several decades ago.5,7 As such, many of
these important lead molecules were evaluated prior to the cloning
of the D3R.1a Remarkably, more recent studies have shown that 3-
PPP (2) and the related N-propyl-3-(3-hydroxyphenyl)pyrrolidine
(3) show significant affinity for the D3R (Fig. 1).8,9 While the clinical
development of D3R-preferring agonists like pramipexole (from an
alternative structural class) overshadowed the earlier interest in
analogues like 2 and 3, we feel that there is still significant oppor-
tunity for further discovery of new selective D3R agonists through
extending SAR studies of the 3-(3-hydroxyphenyl)pyrrolidine
scaffold.
With these considerations in mind, we have been working to
reinvestigate the known 3-(3-hydroxyphenyl)pyrrolidine scaffold
and extend structure–activity relationship (SAR) studies for this
basic core structure for the purpose of developing novel D3R bind-
The nearly identical orthosteric binding site (OBS) and the high
sequence identity (78%) in the transmembrane domain has been
viewed as an impetus to look beyond the primary catecholamine
pharmacophore for achieving selectivity for the D3R over the
D2R.1d–f,10 Analysis of the D3R crystal structure (in complex with
the selective D2/D3 antagonist eticlopride)11 and recent homology
⇑
Corresponding author.
E-mail address: wneuman@siue.edu (W.L. Neumann).
modeling studies have identified differences in
a secondary
https://doi.org/10.1016/j.bmcl.2018.03.084
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
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2
A. Omran et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
To probe the carbon chain-length tolerance of the hydrophobic
region of the SBP we have synthesized a homologous series of race-
mic N-alkyl analogues (5–10 carbons in length) for comparison to
the known N-propyl 3 and N-butyl 4 analogues.6a,9 While the N-
alkyl substituents of the homologous series of may not be
considered true secondary pharmacophores, we hoped this study
would determine the optimal chain length from this specific
pyrrolidine scaffold into the SBP. In addition, since the D3R SBP is
predominantly hydrophobic, we chose this lipophilic N-alkyl
series with the hope of potentially gaining some increase in D3R
affinity and selectivity though resulting hydrophobic interactions
with the alkyl chains. Target compounds were synthesized
according to the reductive alkylation or amide reduction
chemistries outlined in Scheme 1.
D2 Ki = 3.9 - 100 nM
D3 Ki = 0.5 – 8.5 nM
D2 Ki = 137 19 nM
D3 Ki = 132 16 nM
D2 Ki = 68 9 nM
D3 Ki = 52 8 nM
Fig. 1. Dopamine D2/D3 receptor ligands. Pramipexole1(Ref. 1f), 3-PPP 2(Ref. 8d),
Pyrrolidineanalogue 3(Ref. 9).
binding pocket (SBP) which has attracted the attention of a number
of groups for generating selectivity over the D2R.10 The D3R SBP
connects to the orthosteric site through a largely hydrophobic
region (near transmembrane helices 1, 2, and 7) and extends out
toward extracellular loops I and II (which open to the outer aque-
ous space). These structural studies along with comparative ligand
docking analyses, molecular dynamics simulations, and SAR stud-
ies from several groups using the privileged 4-phenylpiperazine
class of selective D3 ligands to occupy the OBS while extending
functionality into the SBP, suggest a longer, linear OBS-SBP orien-
tation in the D3R compared to a bent orientation in the D2R.10,12
To further investigate the 3-(3-hydroxyphenyl)pyrrolidine scaf-
fold for targeting the D3R we envisioned a ligand design based
upon extending functionality from the OBS-binding scaffold into
the SBP to enhance both D3R affinity and selectivity over D2R. This
type of bitopic ligand design has been employed by a number of
groups to afford D3R antagonists and partial agonists with other
core templates.12,13 In addition, there is some literature evidence
that relates allosteric interactions within the SBP via the bitopic
ligand approach to biased signaling.14 Biased signaling leading to
functional selectivity has been shown to govern the tolerance
and slow response termination properties of the D3R15 and new
bitopic ligands maybe particularly useful to more fully investigate
these pathways.
Thus, cinnamate 516 was converted to nitro-ester analogue 6 by
a literature method involving the conjugate addition of nitro-
methane mediated by DBU.17 Compound 6 was converted to the
lactam 7 in one pot by sequential reduction of the nitro-group with
Zn powder in 1 N HCl followed by neutralization and heating to
effect cyclization. The lactam 7 underwent smooth reduction with
lithium aluminum hydride to afford the key 3-(3-methoxyphenyl)
pyrrolidine 8. Reductive alkylation of 8 with pentanal, octanal,
nonanal, and decanal afforded compounds 9a-d. Methyl deprotec-
tion of each of the compounds using boron tribromide afforded the
corresponding phenol analogues 10a-d. The amide reduction route
was devised for derivatives for which the precursor acid chloride
was more economical to purchase than the corresponding alde-
hyde required for the reductive amination route. Thus, for the
amide reduction route key intermediate 8 was acylated under
Schotten-Baumann conditions with hexanoyl and heptanoyl chlo-
rides to afford amides 11a (R2 = pentyl) and 11b (R2 = hexyl),
respectively. These amide derivatives were then converted to ana-
logues 12a and 12b by reduction with lithium aluminum hydride.
Finally, compounds 12a and 12b were deprotected by treatment
Scheme 1. Synthesis of N-alkyl-3-(hydroxyphenyl)pyrrolidinehomologous series, reductive amination route. Reagents and conditions: (a) nitromethane (18 equiv), DBU (5
equiv), 0 °C, 1 h, 20 °C, 16 h, 91%; (b) Zn (23 equiv), 1 N HCl, IPA, 2 h; (c) NaHCO3(to pH ꢀ 7.5), 70 °C, 1 h, 79% over 2 steps; (d) LiAlH4(2 equiv), THF, 0 °C, 1 h, then heated at 65
0 °C, 2 h, 77%; (e) aldehyde (1 equiv), NaBH(OAc)3(1.5 equiv), 20 °C, 16 h, R = n-pentyl, 97%, R = n-octyl, 53%, R = n-nonyl, 58%, R = n-decyl, 59%; (f) BBr3, (2 equiv), CH2Cl2, 0 °C,
1 h, 20 °C, 2 h, R = n-pentyl, 12%, R = n-octyl, 98%, R = n-nonyl, 36%, R = n-decyl, 61%. Amide reduction route. Reagents and conditions: (g) acid chloride (1.1 equiv),
Na2CO3(1.75 equiv), H2O, CH2Cl2, 20 °C, 2 h, R = n-pentyl(hexanoylchloride), 84%, R = n-hexyl (heptanoylchloride), 77%; (d) LiAlH4(2.2 equiv), THF, 0 °C, 1 h, 65 0 °C, 2 h, R = n-
hexyl, 62%, R = n-heptyl, 77%; (f) BBr3, (2.3 equiv), CH2Cl2, 0 °C, 1 h, 20 °C, 2 h, R = n-hexyl, 39%, R = n-heptyl, 44%.
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A. Omran et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
with boron tribromide to afford analogues 13a and 13b,
respectively.
exception of the N-nonyl analogue 10c affording a modest Ki =
98 nM.
Compounds 10a-d, 13a, and 13b were evaluated in receptor
binding assays using stably transfected or transiently transfected
cloned human receptors. Radioligand competition assays were
conducted with [3H]N-methylspiperone for D2R, D3R, and D4R
and [3H]SCH23390 for D1R and D5R. Full experimental details for
binding measurements at these and all other receptors can be
found at the NIMH Psychoactive Drug Screening Program website:
(http://pdspdb.unc.edu/pdspWeb/).18
Analysis of the data from the radioligand binding studies for the
homologous series (N-pentyl through N-decyl) of analogues of the
3-(3-hydroxyphenyl)pyrrolidine scaffold (10a-d, 13a and 13b)
showed several interesting trends (Table 1). The N-butyl ana-
logue6a was included as well. As expected for N-alkyl derivatives
of this scaffold, low affinity for the D1-like receptors (D1R and
D5R) was observed. However, a modest increase in affinity for
the D1R and the D5R was observed in longer chain analogues
10b-d. For the D2-like receptors (D2R, D3R and D4R), a similar
trend of increasing binding affinity with increasing chain length
was observed for all three receptors. However, this series of
analogues shows very low affinity for the D2R in general with the
We were gratified to observe that the series shows much higher
overall affinity for the D3R and D4R over the other dopamine recep-
tors. For both receptors, the N-octyl and N-nonyl analogues, 10b
and 10c show the highest affinity, both converging on single-digit
nanomolar Ki values. Thus, there is no selectivity for D3R over D4R.
However, the best D3R ligand, N-nonyl compound 10c shows a 20-
fold selectivity over the D1R, and 11-fold selectivity over both the
D2R and the D5R. D2/D3 ratios indicate significant selectivity for the
D3R over the D2R for all members of the series.
A similar trend of increasing affinity with increasing chain
length was observed for the 5HT1A receptor. High affinity is first
observed in the N-heptyl analogue 13a (Ki = 19 nM) and continues
through the N-octyl, N-nonyl, and N-decyl series (compounds 10b-
d).
Since the N-nonyl compound 10c showed the highest affinity of
the series for the D3R (Ki = 9 nM), we selected this compound for
preparation of the enantiomeric pyrrolidine analogues (À)-19
and (+)-20. Our goal was to probe the chirality-dependence of
the 3-(3-hydroxyphenyl)pyrrolidine scaffold within the OBS while
maintaining the optimal lipophilic tail length for hydrophobic
Table 1
Homologous study: Binding affinities for dopamine and 5HT1A receptors (Ki, nM).
Compound
D1
D2
D3
D4
D5
D2/D3
8.9
5HT1A
861
323 (5 4 0)b
2877 602(2 4 1)a
324 119
1174 247
1613 884
1805 210
N
H
O
4
542 75
>10,000
131 15
164 23
605 107
>76
326 53
N
H
O
10a
13a
13b
10b
10c
10d
1278 272
597 98
170 37
174 29
128 38
3555 741
369 52
368 68
98 21
162 26
49 5.5
19 2.5
114
5
640 147
438 93
286 60
101 21
143 31
21.9
7.5
272 31
N
N
N
N
N
H
H
H
H
O
O
O
O
11 0.9
5.1 2.5
5.8 0.7
14 1.0
19
2
19.4
10.9
11.3
9.4 0.9
15 1.0
12 6.3
9
1.2
464 87
41 4.8
HO
a
Radioligand binding measurements were performed by the NIMH Psychoactive Drug Screening Program (Ref. 18).
(Ref. 6a).
b
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A. Omran et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
interaction with the SBP. To prepare the chiral N-nonyl analogues
19 and 20 we chose to resolve the racemic key intermediate 8
using a modification of the methodology reported for the resolu-
tion of the related phenylpiperidine analogues (Scheme 2).7a
Thus, pyrrolidine 8 was converted to the N-benzyl analogue 14
by reductive amination. Treatment of a hot methanolic solution
of (+)-dibenzoyl-d-tartaric acid with a solution of 14 in methanol
afforded crystalline material after cooling. Two additional
recrystallizations afforded the (À)-isomer 15 in enantiomerically
engages in a hydrogen bond with Cys-181 on extracellular loop 2
of the D3R. In addition, since Cys-181 participates in a disulfide
bond between extracellular loop 2 and the third transmembrane
domain, and therefore plays
a role in stabilizing the GPCR
structure, hydrogen bond interaction with the backbone
a
carbonyl of Cys-181 may be useful in altering receptor
conformation via the SBP. With these considerations in mind, our
next goal was to determine if this benzamide-Cys-181
interaction could be extended to the 3-(3-hydroxyphenyl)
pyrrolidine scaffold. Thus, we designed compounds 28, 29 and 30
in order incorporate the Mach benzamide secondary
pharmacophore with an overall length similar to WC10 and our
best analogue from the homologous series. Remarkably,
inspection of molecular models indicates that the N-nonyl
compound 10c, the compound from the homologous series with
the highest affinity for the D3R, has an overall length which is
closest to compounds 28, 29 and 30, as well as WC10. In order to
bridge the 3-(3-hydroxyphenyl)pyrrolidine scaffold with the
Mach secondary pharmacophore effectively in this new series the
pure form after isolation as the free base ([
a]
21 = À43 (c, 1.0)).
D
Similarly, enantomerically pure (+)-isomer 17 was obtained
through treatment of the free base isolated from the previous
mother liquor with (À)-dibenzoyl-l-tartaric acid ([
a]
21 = +42 (c,
D
1.0)). Compounds 15 and 17 were hydrogenated using 5%
palladium on carbon in methanol to remove the N-benzyl groups
affording pyrrolidines 16 and 18, respectively. These key chiral
intermediates were then converted to the N-Nonyl analogues 19
and 20, respectively, using the reductive amination route
described in Scheme 1. To confirm optical purity, compound 16
was reacted with (S)-(1-isothiocyanatoethyl)benzene (S1) to
afford a single diastereomeric thiourea S2 derivative. In addition,
compounds needed to employ
a 4-carbon linker from the
pyrrolidine nitrogen to the benzamide. It is interesting to note
that this linkage length has been found to offer optimal results
with the phenylpiperazine scaffold and other secondary
pharmacophores for D3R affinity.13b
racemic compound
8
was also reacted with (S)-(1-
isothiocyanatoethyl)benzene (S1) to afford a 50:50 mixture of
diastereomeric thioureas (S2-diastereomeric mixture) for
comparison (see Supplementary material for characterization
data and NMR analyses for these compounds).
Using the information obtained from the homologous series we
also became interested in preparing 3-(3-hydroxyphenyl)-pyrro-
lidine N-substituents with similar overall penetration into the
SBP but further functionalized for increased interactions. To this
end we were drawn to a report from the Mach group describing
D3R ligands with benzamide-based secondary pharmacophores.12a
Compounds in this series such as WC10 (Table 2) showed very high
affinity and selectivity for the D3R over the D2R. To account for the
high affinity, it was proposed that the benzamide-NH of WC10
Synthesis of the benzamide analogues is presented in Scheme 3.
The commercially available 4-aminobutyraldehyde diethyl acetal
21 was Boc-protected to afford compound 22. Deprotection of
the acetal under mild acidic hydrolysis afforded the Boc-protected
cyclic hemi-aminal 23. Reductive amination of key pyrrolidines 8,
16, and 18 using 23 as the aldehyde source (formed in situ), fol-
lowed by acidic deprotection of the Boc- group afforded the N-
(4-aminobutyl)pyrrolidine derivatives, 24, 25 and 26. EDC coupling
of these intermediates with 4- dimethylaminobenzoic acid 27 fol-
lowed by cleavage of the methyl group with boron tribromide
afforded compounds 28, 29 and 30.
Scheme 2. Synthesis of chiral N-alkyl-3-(hydroxyphenyl)pyrrolidineanalogues, resolution and reductive amination route. Reagents and conditions: (a) benzaldehyde (1
equiv), NaBH(OAc)3(1.5 equiv), 20 °C, 16 h, 81%; (b) (2S, 3S)-(+)-dibenzoyl- -tartaric acid, MeOH, then NaOH, 42%; (c) (2R, 3R)-(À)-dibenzoyl- -tartaric acid, MeOH, then
NaOH, 35%; (d) H2(balloon), 5% Pdon carbon, MeOH, 95% for 16, 89% for 18.
D
L
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A. Omran et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
Table 2
Chiral and N-functionalized ligands: Binding affinities for dopamine and 5HT1A (Ki, nM).
Compound
Compound
D1
D2
D3
9
2.4 0.33
12 1.6
D4
D5
5HT1A
Rac-10c
(À)-19
(+)-20
174 29
181 47
>10,000
98 21
42 7.7
62 11
1.2
5.8 0.7
5.5 23
27 15
101 21
227 59
639 120
15 1.0
48 6.7
115 16
Rac-28
(À)-29
(+)-30
831 116
4589 847
>10,000
343 63
360 68
345 72
14 2.2
14 2.6
27 4.4
54 10
135 60
>10,000
312 74
955 477
>10,000
110 23
160 27
328 74
aRadioligand binding measurements were performed by the NIMH Psychoactive Drug Screening Program (Ref. 18).
Scheme 3. Synthesis of racemic and chiral N-benzamidobutyl-3-(hydroxyphenyl)pyrrolidineanalogues. Reagents and conditions: (a) Bocanhydride (1 equiv), TEA, THF, 0–5
°C then RT, 3.5 h, 95%; (b) AcOH, H2O, HCl, 26 h, 81%; (c) NaBH(OAc)3(1.5 equiv), 20 °C, 16 h; (d) 4 N HClin dioxane, CH2Cl2, 51% for 24 from8, 90% for 25 from16, 91% for 26
from18(for 2 steps); (e) EDCÅHCl, HOBtÁH2O, TEA, DMF 16 h; (f) BBr3, (2.3 equiv), CH2Cl2, 0 °C, 1 h, 20 °C, 21% for 28from 24, 29% for 29from 25, 35% for 30from 26(for 2 steps).
Radioligand binding data for the racemic and chiral N-nonyl and
benzamide analogues are presented in Table 2. Both series show a
strong preference for the (À)-enantiomer for high affinity toward
the D3R and the D4R. For the N-nonyl series, the (À)-enantiomer
19 shows high affinity for the D3R (Ki = 2.4 nM) with a 75-fold
selectivity over the D1R, 17.5-fold selectivity over the D2R, and a
95-fold selectivity over the D5R. A modest 2-fold selectivity over
the D4R was also observed. Similarly, for the 5HT1A receptor, higher
affinity appears to lie in the (À)-enantiomer 19. Unfortunately, the
potential additional interaction of the benzamide NAH with the
carbonyl of Cys-181 was not achieved and/or did not contribute
to further enhanced binding affinity over the N-nonyl-probe ana-
logues. Thus, the (À)-enantiomer 29 afforded a Ki = 14 nM whereas
the (+)-enantiomer 30 showed a Ki = 27 nM for the D3R.
While the OBS for all dopamine receptors appears to have some
preference for binding the (À)-enantiomer of the 3-(3-hydrox-
yphenyl)pyrrolidine scaffold, the (+)-isomers in both the N-nonyl
and benzamide series still afford significant binding affinity for
the D3R in particular. In fact, while the (À)-enantiomers are higher
affinity ligands, the (+)-enantiomers are considerably more selec-
tive for the D3R. Remarkably, the (+)-benzamide analogue 30
shows good binding affinity for the D3R (Ki = 27 nM), with a 13-
fold selectivity over D2R, and > 370-fold selectivity over the D1R,
D4R and D5R.
pyrrolidine scaffold in the OBS to the SBP of the D3R. From this ser-
ies we have identified the N-nonyl analogue as having the highest
binding affinity for the D3R. Key scaffold intermediate 8 was
resolved and the N-nonyl enantiomers were prepared following
the information gained by the homologous series work. The (À)-
isomer 19 afforded the highest affinity for the D3R with good selec-
tivity over the D1R, D2R and D5R and slight selectivity over D4R. N-
Benzamidobutyl analogues 28–30 were also prepared to attempt
to engage Cys-181 in the SBP to enhance affinity and selectivity
for the D3R. Unfortunately, no gain in affinity was observed for this
series but selectivity for the D3R was further improved. For the
benzamide series the highest affinity for the D3R was also found
in the (À)-isomer, compound 29. This study reinvestigates and fur-
ther expands the SAR of the 3-(3-hydroxyphenyl)pyrrolidine scaf-
fold for dopaminergic activity. Future studies will involve the
development of new N-functionality for further probing the SBP
of the D3R.
Acknowledgments
This work was supported by the SIUE School of Pharmacy
Research Grant (2016). Radioligand binding measurements were
conducted by the NIMH Psychoactive Drug Screening Program
website: (http://pdspdb.unc.edu/pdspWeb/). High Resolution Mass
Spectrometry was performed by the University of Notre Dame
Mass Spectrometry and Proteomics Facility.
In summary, we have synthesized a homologous series of N-
alkyl-3-(3-hydroxyphenyl)pyrrolidine analogues to probe the
chain-length requirements of functionality extending from the
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A. Omran et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
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Please cite this article in press as: Omran A., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.03.084