Systematic synthesis of novel phosphoglycolipid analogues as potential agonists of GPR55

Article abstract of DOI:10.1039/d0ob01756f

Rhodopsin-like G protein-coupled receptor (GPCR) GPR55 is attracting attention as a pharmaceutical target, because of its relationship with various physiological and pathological events. Although GPR55 was initially deorphanized as a cannabinoid receptor,

Full text of DOI:10.1039/d0ob01756f

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Systematic synthesis of novel phosphoglycolipid
analogues as potential agonists of GPR55†
Cite this: DOI: 10.1039/d0ob01756f
b
Junpei Abe, a Adam T. Guy, b Feiqing Ding, c Peter Greimel,
a,d
Yoshio Hirabayashi,d Hiroyuki Kamiguchi b and Yukishige Ito
*
Rhodopsin-like G protein-coupled receptor (GPCR) GPR55 is attracting attention as a pharmaceutical
target, because of its relationship with various physiological and pathological events. Although GPR55 was
initially deorphanized as a cannabinoid receptor, lysophosphatidylinositol (LPI) is now widely perceived to
be an endogenous ligand of GPR55. Recently, lysophosphatidyl-β-D-glucoside (LPGlc) has been found to
act on GPR55 to repel dorsal root ganglion (DRG) neurons. In this study, we designed and synthesized
various LPGlc analogues having the squaryldiamide group as potential agonists of GPR55. By the axon
turning assay, several analogues exhibited similar activities to that of LPGlc. These results will provide valu-
able information for understanding the mode of action of LPGlc and its analogues and for the discovery
of potent and selective antagonists or agonists of GPR55.
Received 25th August 2020,
Accepted 8th October 2020
DOI: 10.1039/d0ob01756f
rsc.li/obc
agonist CP55940 (2) to be a GPR55 agonist and a GPR55
Introduction
partial agonist/antagonist, respectively (Fig. 1).8a However, as
G protein-coupled receptors (GPCRs) constitute a group of these compounds were shown to exhibit limited selectivity to
largest transmembrane proteins having a 7-transmembrane GPR55, efforts have been made to seek novel chemotypes.
architecture.1 These proteins are promising pharmaceutical Along this line, the library screening of non-cannabinoids
targets,2 in light of their diverse biological functions associ- resulted in the discovery of potent agonists such as ML 184
ated with signal transductions. Accordingly, a number of mole- (3)9 and GSK494581A (4).10 More recently, other chemotypes,
cules targeting them have been developed to date. Continuous such as 5,11 612 and 7,13 have been reported to be promising
effort to deorphanizing GPCRs will help elucidate their func- candidates. On the other hand, the potential utility of com-
tions and discover pharmaceutically relevant molecules.
pounds based on endogenous agonists has been poorly
Human GPR55 is a rhodopsin-like class A GPCR consisting addressed.
of 319 amino acids.3 Its homology with typical cannabinoid
In 2009, Oka et al. proposed lysophosphatidylinositol (LPI;
receptors CB1 and CB2 was found to be rather low, being 13% 8a)14 to be an endogenous agonist of GPR55 (Fig. 2).15 GPR55
and 14%, respectively. Receptors having higher homology to is known to be present in various organs and tissues such as
GPR55 are GPR35 (27%), P2Y (29%), GPR23 (30%), CCR4 the brain,2,16 gastrointestinal tract,2,17 pancreas18 and adipose
(23%), LPA4 (30%) and LPA5 (30%).4 Initially, GPR55 was deor- tissue,19 and implicated to modulate diverse physiological and
phanized as a putative receptor for cannabinoids.5,6
pathological events such as central nervous system (CNS) func-
To deepen the understanding of GPR55 functions, studies tion,20 pain,21 inflammation,22 metabolic regulation,19 cell
have been carried out to develop ligands possessing high migration and proliferation.23 However, the biological func-
potency and selectivity.7 For instance, A. Kapur et al. reported tions of GPR55 are still controversial,24 as the precise analysis
the CB1 inverse agonist SR141716A (1) and the cannabinoid of its properties has been hampered by various reasons. For
instance, its activation often stimulates multiple signal trans-
duction pathways,8,25 and its functional selectivity (or biased
agonism)26 and cross-agonism by heteromerization of GPR55
with CB127 or CB228 further complicate the situation.
Moreover, the results obtained by using different cell lines,
ligands and endpoints assay8,15,17,25a,b,29 are often difficult to
reconcile.
aGraduate School of Science, Osaka University, Toyonaka, 560-0043, Japan
bRIKEN Center for Brain Research, Wako, Saitama, 351-0198, Japan
cSchool of Pharmaceutical Sciences (Shenzhen), SunYat-sen University, Guangzhou
510275, China
dRIKEN Cluster for Pioneering Research, Wako, Saitama, 351-0198, Japan.
E-mail: yukito@riken.jp
Whilst LPI has been studied extensively as an endogenous
ligand of GPR55 for many years, our study revealed that lyso-
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob01756f
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Fig. 1 Reported agonists of GPR55.
Fig. 2 (A) Structures of GPR55 endogenous ligands (8a, 8b and 9a) and synthetic analogues 9b and 10. (B) General synthetic route to the LPGlc
analogue possessing a SDA moiety as a surrogate of phosphodiester.
phosphatidyl-β-D-glucoside (LPGlc; 9) acts on sensory neuron through GPR55 activation.30 Intriguingly, while its galactose
axons as a chemorepulsive guidance cue released from the analogue was inactive, the ether analogue 9b exhibited a
radial glia in the developing spinal cord to repel nerve growth similar activity,31 indicating the precise recognition of the
factor (NGF)-responsive dorsal root ganglion (DRG) neurons glucose moiety.32 As the utilization of LPGlc or its analogues
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would be an attractive tactic to specifically regulate GPR55,
facile access to such molecules is needed.
Results and discussion
The systematic synthesis of phospholipid derivatives related The structures of our targets are shown in Fig. 3. These com-
to LPGlc would be a demanding task because of the compli- pounds are characterized by structural alterations from 10, in
cated synthetic schemes.31,33 Based on this, we embarked on terms of the presence of aryl substituents (11a–f), unsaturation
the synthesis of novel LPGlc analogues possessing a squaryl- (11g,i), and the site of glycerol substitution (11h,i), or C6 fluor-
diamide (SDA) group as a surrogate of phosphodiester that ination of the glucose residue (11j). The design of 11a–f was
links sugar and lipid moieties.34 We predicted that the syn- hinted by the docking study37 which proposed the presence of
thesis of analogues possessing a SDA moiety would be a π–π stacking interaction between Phe (F6.55) of GPR55 and the
logical strategy to create LPGlc analogues, as SDA has signifi- dimethylpheyl group of ML 184 (3), while the same Phe
cant polarization and hydrogen bond acceptor activity35 that residue was suggested to attract a LPI alkyl chain by van der
mimic that of phosphodiester. Our preceding study found the Waals interaction. On the other hand, as 2-arachidonoyl LPI
prototypical compound 10 featuring an identical chain length (8b) was reported to be the most potent among the endogen-
compared to the natural LPGlc that exhibited an activity ous agonists of GPR55,36 we were interested in knowing the
similar to that of LPGlc.34
effects of unsaturation along with the site of glycerol substi-
The scheme of synthesizing SDA analogues is highly attrac- tution, and we designed compounds 11g, 11h, and 11i. In
tive in terms of its technical simplicity. Namely, the formation addition, γ-diol 11k was also synthesized as an analogue
of glucosylamine (A) from glucose and the subsequent reaction having an extra hydroxy group.
with dialkyl squarate can be performed without the protection
To approach the aryl modified analogues (11a–f), the prepa-
of sugar moieties. The resultant amide-ester (B) can be diversi- ration of requisite alkyl halides and conversion to β-hydroxy
fied easily to various analogues by coupling with the corres- amines were conducted as shown in Schemes 1 and 2. Namely,
ponding amino glycerol derivatives (C). We deemed the design 1,10-decane-, 1,13-tridecane- and 1,15-pentadecane-diols (12a–
to be also suitable in addressing the effect of the site of gly- c) were monoalkylated with benzyl or naphthylmethyl bromide
cerol substitution, because, unlike naturally occurring LPI and to afford 13a–f, which were converted to bromides (14a–f)
LPGlc, the possibility of acyl migration can be rigorously under Appel reaction conditions. Lower yields of 13c and 13f
eliminated.36
were due to the limited solubility of the precursor 12c even at
In this study, we demonstrated that our scheme can be elevated temperatures. On the other hand, arachidonyl
flexibly applied to the synthesis of various LPGlc bromide (17), a precursor for 11g, was synthesized from arachi-
analogues differing in the structures of the sugar and lipid donic acid (15) in two steps through LAH reduction and bromi-
components.
nation of the resultant alcohol (16).38
Fig. 3 LPGlc analogues with varying alkyl side chains or glucose parts.
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Scheme 1 Reagents and conditions: (a) NaH, DMF, 60 °C, overnight; (b) CBr4, PPh3, THF, rt, 2h; (c) LAH, THF, 0 °C; (d) CBr4, PPh3, THF, rt; (e) NaH,
DMF, rt; (f) TBAF, AcOH, THF, rt, overnight; (g) H2N-NH2·H2O, MeOH, reflux, 2h (21a–f) or H2N-NHMe, MeOH, reflux, 2h (21g).
Scheme 2 Reagents and conditions: (a) Thiourea, MeOH, rt, 24 h; (b) NaOAc, AcOH, DMF, 100 °C, 38 h; (c) 1 N HCl-MeOH/dioxane, rt, 2 h; (d) NaH,
DMF, rt; (e) H2N-NH2·H2O, MeOH, reflux, 2 h; (f) H2N-NHMe, MeOH, reflux, 2 h.
The coupling of the bromides (14a–f, 17) with the thiol 1834
On the other hand, sn-2-thiol derived amines 27a and 27b
was followed by the removal of TBS and phthalimide groups to were synthesized as shown in Scheme 2. Namely, the ring-
afford the corresponding hydroxy amines (21a–f) (Scheme 1). opening of thiirane (23) obtained from epoxide (22)41 gave 24,
Due to the possible risk of reducing olefinic linkages by hydra- which was deacetylated under acidic conditions to afford the
zine treatment,39 methyl hydrazine was used for the de- thiol 25. The alkylation of its sn-2 position by eicosyl and ara-
protection of the arachidonyl derivative (20g).40
chidonyl bromide gave 26a and 26b, respectively, which were
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Scheme 3 Reagents and conditions: R-NH2, DIPEA, EtOH, rt, overnight. (*) The reaction was conducted at 70 °C.
this particular case, the isolated yield of the product was quite
low because its poor solubility complicated the purification.
Among the LPGlc analogues obtained in this study, com-
pounds 11c, 11i, 11h, 11g, and 11j were selected to estimate
their activities by means of the axon turning assay, in compari-
son with the previously reported LPGlc analogues 1034 along
with the ether LPGlc, an analogue having the closest biological
activity to that of native LPGlc31 (Fig. 4). The benzylated com-
pound 11c exhibited an activity similar to that of 10. While no
positive effect of the introduced aromatic substituent was
observed, this result suggests the possibility of introducing
various substituents to the terminal of the alkyl chain of com-
pound 10, possibly for the development of clickable, cross-
linking, or fluorescently labelled ligands of GPR55. Somewhat
to our surprise, the 1-arachidonyl analogue 11g exhibited
markedly reduced activity compared to 2-arachidonyl
derivative 11i. 11i exhibited a similar activity to that of 10, and
its fully saturated congener 11h was nearly inactive. The
6-fluoro analogue (11j) turned out to be inactive,
suggesting that the presence of a 6-hydroxy group is essential
for binding to GPR55, potentially due to the hydrogen
bonding interaction with Y3.22.37 Therefore, although unsa-
turation of the alkyl chain would lower the energy of the spiral
conformation that is needed to fit into the binding pocket of
GPR55,37 the effect of unsaturation seems to depend on the
substitution site.
Fig. 4 Biological assay of the chemotropic activity of LPGlc analogues.
Chemorepulsion induced by the microscopic concentration gradient of
compounds 11c–11j, compared to that induced by the previously
characterized ligands ether-LPGlc and 10 and vehicle control.
Compounds were tested at an in-pipette concentration of 20 µM except
ether-LPGlc which was tested at 10 µM. Bars show mean turning angle
SEM, and the numbers in parentheses indicate the number of axons
tested. Biological assay conditions are described in full in the Materials
and methods section.†
Conclusions
By using glycosylamine derived squarylamide as a common
precursor, various LPGlc analogues were synthesized by coup-
converted to 27a and 27b after the deprotection of the phthali- ling with a series of amino glycerol derivatives. By the axon
mide groups.
turning assay, sn-2 arachidonylated (11i) and O-benzyl-substi-
Finally, the common precursor 28a was diversified to 11a–i tuted (11c) analogues were suggested to be promising as
by reacting it with the corresponding amines in the presence potential agonists of GPR55. A more systematic structure–
of DIPEA as shown in Scheme 3. The 6-fluoro analogue 11j was activity relationship study is underway, which will help under-
synthesized from 28b in an analogous manner. However, in stand the mode of interactions between LPGlc and GPR55 and
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result in the discovery of highly potent agonists or antagonists
of GPR55.
Reports from the NIH Molecular Libraries Program, National
Center for Biotechnology Information, 2011, https://www.
ncbi.nlm.nih.gov/books/NBK66152/.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We thank Dr Takemichi Nakamura (RIKEN CSRS) for mass
spectroscopy measurements, Dr Akihiro Ishiwata (RIKEN CPR)
for helpful suggestions, Dr Yasuhiro Kajihara (Osaka
University) for his generous support, and Akemi Takahashi for
the technical assistance. This work was supported by Grant-in-
Aid for Scientific Research 16H06290 (Y. I.), 20K06884
(A. T. G.), and 16K08259 (P. G.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan,
AMED-CREST Grant No. 20gm0910006h0005 (H. K.), the
Mizutani Foundation for Glycoscience (P. G.) and the
Glycolipidologue Program of RIKEN (P. G., Y. H., H. K.).
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