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 (IC₅₀ 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 (IC₅₀ 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 (IC₅₀ 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 (IC₅₀ 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 (IC₅₀ 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 (IC₅₀ 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 (IC₅₀ 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 (IC₅₀ 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 (IC₅₀ 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