Stereoselective Synthesis and Antiallodynic Activity of 3-Hydroxylated Paroxetines

Article abstract of DOI:10.1002/cmdc.202000674

The design, stereoselective synthesis and in vivo antiallodynic activity of four novel paroxetine analogs, named 3-hydroxy paroxetines (3HPXs), is reported herein. Among the novel synthesized compounds, three showed an antiallodynic effect, while (R,R)-3HPX was found to be 2.5 times more bioactive than (-)-paroxetine itself in neuropathic rats. Consequently, the current investigation not only discloses a novel promising analgesic drug, but also reveals that functionalization at the C3 position of paroxetine could be as effective as the common functionalization at either C4 or within the sesamol group.

Full text of DOI:10.1002/cmdc.202000674

Accepted Article
Title: Stereoselective Synthesis and Antiallodynic Activity of 3-
Hydroxylated Paroxetines
Authors: Fernando Sartillo-Piscil, Delfino Chamorro-Arenas, Giovanna
Salgado-Moreno, Liliana Martinez-Mendieta, Beatriz Godínez-
Chaparro, and Leticia Quintero
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To be cited as: ChemMedChem 10.1002/cmdc.202000674
Link to VoR: https://doi.org/10.1002/cmdc.202000674
01/2020

10.1002/cmdc.202000674
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Stereoselective Synthesis and Antiallodynic Activity of 3-
Hydroxylated Paroxetines
Delfino Chamorro-Arenas,[a] Giovanna Salgado-Moreno,[b] Liliana Martinez-Mendieta,[a] Leticia
Quintero,[a] Beatriz Godínez-Chaparro,* [b] and Fernando Sartillo-Piscil*[a]
Dedication ((optional))
[a]
[b]
Delfino Chamorro-Arenas, Dr. Leticia Quintero, Dr. Liliana Martinez-Mendieta, and Prof. Fernando Sartillo-Piscil
Facultad de Ciencias Químicas
Benemérita Universidad Autónoma de Puebla
14 Sur Esq. San Claudio, Col. San Manuel S/N, 72570, Puebla, México.
E-mail: fernando.sartillo@correo.buap.mx
Giovanna Salgado-Moreno, and Dr. Beatriz Godínez-Chaparro.
Sistemas Biológicos, División de Ciencias Biológicas y de la Salud.
Universidad Autónoma Metropolitana-Xochimilco.
Calzada de Hueso 1100, Col. Villa Quietud, 04960, Ciudad de México, México.
E-mail: bgodinez@correo.xoc.uam.mx
Supporting information for this article is given via a link at the end of the document.
synthesis of paroxetine analogs as potential analgesic drugs has
not been reported yet.
Abstract: The design, stereoselective synthesis and in vivo
antiallodynic activity of four novel paroxetine analogs, named 3-
hydroxy paroxetines (3HPXs), is reported. Among the novel
synthesized compounds, three of them showed antiallodynic effect,
while the (R,R)-3HPX resulted to be 2.5 times more bioactive than (-
)-paroxetine itself in neuropathic rats. Consequently, the current
investigation not only discloses a novel promising analgesic drug,
but also reveals that functionalization at the C-3 position of
paroxetine could be as effective as the common functionalization at
either C-4 or within the sesamol group.
Figure 1. (-)-Paroxetine and two representative bioactive analogues
Neuropathic pain is caused by a lesion or disease of the
somatosensory nervous system,1 and affects around 6.5 to 10 %
of the general population.2 Although this type of pain can be
either spontaneous or evoked, it is possible to differentiate
various types of alterations as a pain response to a normally
nonpainful stimulus (allodynia) or as an increased response to a
painful stimulus (hyperalgesia).3 It is known that neuropathic
pain is associated with a negative impact on the quality of life
and there is a modest efficacy response to existing analgesics
like non-steroidal anti-inflammatory drugs or opioids.4 In contrast,
antidepressants such as amitriptyline, duloxetine, fluoxetine or
paroxetine, and antiepileptics like gabapentin and pregabalin,
have shown efficacy under various neuropathic pain
conditions.5,6
Scheme 1. Proposed synthesis of four 3-hydroxyparoxetines (3HPXs) from
(S)-1
In this regard, (-)-paroxetine is a potent selective serotonin
reuptake inhibitor (SSRI), which was initially prescribed for the
treatment of depression and anxiety disorders,7 and later, has
proved to be effective for further clinical disorders.8,9 Since
SSRIs is a family of antidepressants that inhibits the reuptake of
5-HT into the presynaptic neuron once the 5-HT has been
released affecting the duration and intensity of the 5-HT
Consequently, we envisioned the synthesis and the antiallodynic
study of four novel analogs of paroxetine from which they
feature a hydroxyl group at C-3 position. With this structural
modification, we anticipated effective biological activity either by
increasing the solubility of the analogues in aqueous media or
by means of an effective hydrogen bond interaction with the
receptor.20,21 To this end, we designed the synthesis of four 3-
hydroxylated paroxetines (3HPX) from chiral dehydropiperidine
(S)-122 (Scheme 1).
communication,10-13
paroxetine
significantly
attenuates
mechanical allodynia and thermal hyperalgesia in different
model of neuropathic pain.6,14-17
Although various paroxetine analogs have been synthesized,
such as CCG-206584618 and femoxetine19 (inhibitor of G-
protein-coupled receptor kinase
2
and antidepressant,
respectively, Figure 1), to the best of our knowledge, the
1
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Scheme 2. Synthesis route of 3-hydroxylated paroxetine in the hydrochloride form [3HPX]HCl
Scheme 3. Regio- and stereoselective epoxide-ring-opening with retention of the configuration
2
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Figure 2. Time course of the antiallodynic effect of intraperitoneal (i.p.) when paroxetine (PPX) is administrated in neuropathic rats (A). Bars show the maximum
possible effect (%MPE, B). Data are expressed as mean ± S. E. M. of six animals. *P < 0.05 versus SNL group and #P < 0.05 versus sham group was
determinated by one-way ANOVA followed by Tukey test
Figure 3. Time course of the antiallodynic effect of (R,R)-3HPX (A), (R,S)-3HPX (C), (S,R)-3HPX (E) and (S,S)-3HPX (G). Data are presented as 50% withdrawal
threshold (A, C, E, G) or as % of maximum possible effect (%MPE, B, D, F, H). Data are the mean ± S.E.M., n = 6 per group. *P < 0.001 vs SNL, #P <0.001 vs
sham as determinate by one-way ANOVA followed by Tukey test
3
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Synthesis
or mechanical hyperalgesia12 in neuropathic-pain models.
The synthesis of 3HPXs is depicted in Scheme 2.
Diastereomeric glycidic amides 2a and 2b were obtained in high
yield, but moderate diastereomeric ratio from (S)-1 by applying a
modified tandem oxidation of allyl amines to glycidic amides
protocol.23 The modification consists in the use of cyclohexene
(C6H10) as electrophilic scavenger instead of 2-methyl-2-butene.
Regio- and stereoselective ring-opening of glycidic amides 2a
and 2b with the corresponding Grignard reagent (p-F-C6H4MgBr)
via a SN2 displacement to tertiary alcohols 3a and 4bb,
respectively, was achieved by employing CuBr•SMe2 as catalyst
(e. g., 2a to 3a via A; see Scheme 3).[22] On the other hand, ring-
opening of epoxyamides 2a and 2b with retention of the
configuration to 3aa and 4b, respectively, was achieved by using
the same Grignard reagent but different cupper catalyst (CuI).
The retention of the configuration at C-4 can be explained in
terms of an initial SN2 epoxide-ring-opening reaction mediated
by CuI to give a transient trans-halohydrin followed by a
subsequent SN2 subtitution with the aryl cuprate to give the
corresponding alcohols 3aa from 2a and 4b from 2b (e. g., 2a to
3aa via B; see Scheme 3).[22] The four tertiary alcohols 3a, 3aa,
4b and 4bb were subjected to carbonyl reduction with LiAlH4 to
give 5a, 5aa, 6b and 6bb, respectively, in high chemical yields.
Finally, removal of benzyl group of each 3-hydoxy piperidines 5a,
5aa, 6b and 6bb with H2 and Pd(OH)2 under acidic media (4M,
HCl), provided the target products (R,R)-3HPX, (R,S)-3HPX,
Furthermore,
paroxetine
produced
antiallodynic
and
antihyperalgesic effect in diabetic rats.13,24 Consequently, given
the promising results obtained with (R,R)-3HPX, we anticipate
this novel synthetic alkaloid can be seen as a potential drug for
the treatment of neuropathic pain.
In summary, we have achieved a concise asymmetric synthesis
and studied the antiallodynic effect of four novel synthetic
alkaloids from which one of them resulted to be 2.5 time more
bioactive than (-)-paroxetine in neuropathic rats. Although it is
clear that the position and orientation of the hydroxyl group
placed at the C-3 position plays a crucial role in the biological
activity, we have not had further evidence to prove it yet, albeit
further experimental and computational studies are underway to
investigate the action mechanism of this novel highly bioactive
synthetic alkaloid.
Acknowledgements
The authors thankfully acknowledge Consejo Nacional de
Ciencia y Tecnología (CONACyT). Grant Number: A1-S-21450.
Partial support was provided by BUAP-VIEP.
(S,R)-3HPX,
hydrochloride forms (Scheme 2).
and
(S,S)-3HPX,
respectively,
in
their
Keywords: allodynia • neuropathic pain • paroxetine •
stereoselective synthesis • alkaloids
Pharmacology: antiallodynic effect of paroxetine and
paroxetine analogues in neuropathic rats.
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(S,S)-3HPX (Figure 3G and 3H) did not show antiallodynic effect
at any tested doses.
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COMMUNICATION
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A novel synthetic alkaloid named as R,R-3HPX is introduced as a promising analgesic drug.
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