16 research outputs found
Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders
Despite being an
old molecule, capsaicin is still a hot topic in the scientific community,
and the development of new capsaicinoids is a promising pharmacological
approach in the management of skin disorders related to inflammation
and pruritus. Here we report the synthesis and the evaluation of capsaicin
soft drugs that undergo deactivation by the hydrolyzing activity of
skin esterases. The implanting of an ester group in the lipophilic
moiety of capsaicinoids by the Passerini multicomponent reaction affords
both agonists and antagonists that retain transient receptor potential
vanilloid 1 channel (TRPV1) modulating activity and, at the same time,
are susceptible to hydrolysis. The most promising antagonist identified
shows in vivo anti-nociceptive activity on pruritus and hyperalgesia
without producing hyperthermia, thus validating it as novel treatment
for dermatological conditions that implicate TRPV1 channel dysfunction
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain
Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity
TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of <i>N</i>,<i>N</i>′-dibenzyl tryptamine <b>1</b>, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative <b>14</b> was identified as a potent (IC<sub>50</sub> 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, <b>14</b> showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain