Synthesis, in Vitro, and in Cell Studies of a New Series of [Indoline-3,2′-thiazolidine]-Based p53 Modulators

Analogues of the previously described spiro­[imidazo­[1,5-<i>c</i>]­thiazole-3,3′-indoline]-2′,5,7­(6<i>H</i>,7a<i>H</i>)-trione p53 modulators were prepared to explore new structural requirements at the thiazolidine domain for the antiproliferative activity and p53 modulation. In cell, antiproliferative activity was evaluated against two human tumor cell lines. Derivative 5-bromo-3′-(cyclohexane carbonyl)-1-methyl-2-oxospiro­[indoline-3,2′-thiazolidine] (<b>4n</b>) emerged as the most potent compound of this series, inhibiting in vitro 30% of p53–MDM2 interaction at 5 μM and the cell growth of different human tumor cells at nanomolar concentrations. Docking studies confirmed the interactions of <b>4n</b> with the well-known Trp23 and Phe19 clefts, explaining the reasons for its binding affinity for MDM2. <b>4n</b> at 50 nM is capable of inducing the accumulation of p53 protein, inducing significant apoptotic cell death without affecting the cell cycle progression. Comparative studies using nutlin in the same cellular system confirm the potential of <b>4n</b> as a tool for increasing understanding of the process involved in the nontranscriptional proapoptotic activities of p53

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