Evaluation of N-substitution in 6,7-benzomorphan compounds

Pasquinucci, Lorella; Prezzavento, Orazio; Marrazzo, Agostino; Amata, Emanuele; Ronsisvalle, Simone; Georgoussi, Zafiroula; Fourla, Danai-Dionysia; Scoto, G.M.; Parenti, Carmela; Aricò, Giuseppina; Ronsisvalle, Giuseppe

doi:10.1016/j.bmc.2010.06.005

Cited by 36 publications

(52 citation statements)

References 25 publications

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“…In comparison to the respective previously synthesized and in vitro evaluated N -amido series ( Figure 1 ), an opposite trend emerged [ 10 ]. Indeed, the shorter N -acetamido spacer produced a significant loss of MOR affinity relative to their N -propanamido homologs.…”

Section: Resultsmentioning

confidence: 60%

“…The synthesis of the novel compounds 5a – d and 6a – d was carried out as illustrated in Scheme 1 . Amides 1a – d and 2a – d were prepared by acylation of the respective amines with 2-chloroacetyl chloride and 3-bromopropionyl chloride, respectively, and compounds 3a – d and 4a – d were obtained by alkylation of cis -(−)-(1 R ,5 R ,9 R )- N -normetazocine with the respective amides, as previously reported [ 10 , 14 ]. Then, reduction of compounds 3a – d and 4a – d with diborane in anhydrous THF provided the final compounds 5a – d and 6a – d .…”

Section: Resultsmentioning

confidence: 99%

“…Our results corroborated a plethora of experimental data [ 5 , 7 , 8 ] revealing the unpredictability of pharmacological properties conferred by N -substituents on (−)- cis - N -normetazocine scaffold. For instance, the introduction at the basic nitrogen of an aromatic ring and/or alkyl residues linked by an N -acetamido spacer was detrimental for opioid receptors affinity (K i MOR 722–2930 nM, K i DOR > 5000 nM, K i KOR 335–5000 nM) [ 10 ]. Contrarily, aromatic ring and/or alkyl residues linked by the N -propanamido spacer, as well as the presence of a secondary amido group, improved opioid interaction mainly at MOR [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we synthesized a series of compounds by introducing at the N -substituent of cis -(−)- N -normetazocine an aromatic ring and/or alkyl residues linked by an N -propanamido or N -acetamido spacers ( Figure 1 ) [ 10 ]. Among them, the multitarget opioid ligand LP1, featured by an N -phenylpropanamido substituent, possessed affinity and intrinsic activity for MOR (K i = 0.83 nM, IC 50 = 4.8 nM) and DOR (K i = 29.1 nM, IC 50 = 12 nM).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists

et al. 2018

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The opioid pharmacological profile of cis-(−)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a–d and 6a–d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(−)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(−)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.

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Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists

et al. 2018

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“…There exist two different σ receptors namely Sigma-1 (σ 1 ) and σ 2 receptors distinguished by structure, biological functions and ligands sensitivity. Indeed, σ 1 binding sites display high affinity for dextro benzomorphan enantiomers like (+)-pentazocine, while opioid receptors bind levo isomers [ 14 – 16 ]. Small molecules that bind to the σ receptor (σ ligands or σ-modulating drugs) have many potential functions and are used in diagnostic tumor imaging [ 17 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

et al. 2017

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Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200-1500 new cases occurring per year in the United States. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs and no clinically significant chemotherapeutic protocol is so far available. The aim of the present study was to test the effect of various σ 1 and σ 2 receptor ligands as a possible pharmacological strategy for this rare tumor. Human uveal melanoma cells (92.1) were treated with various concentrations of different σ 2 ligands (haloperidol and haloperidol metabolite II) and σ 1 ligand ((+)-pentazocine) at various concentrations (1, 10 and 25 μM) and time points (0, 4 h, 8 h, 24 h and 48 h). Cell proliferation and migration were evaluated respectively by continuous cell monitoring by xCELLigence analysis, clonogenic assay and wound healing. Apoptosis and autophagy were also measured by cytofluorimetric and microscopy analysis. Our results showed that σ 2 receptor ligands significantly reduced cell proliferation whereas (+)-pentazocine exhibited opposite results. All tested ligands showed significant decrease in cell migration. Interestingly, both σ 1 and σ 2 receptor ligands showed significant increase of autophagy and apoptosis at all concentrations. Taken all together these results suggest that sigma receptors mediates opposite biological effects but they also share common pharmacological effect on apoptosis and autophagy in uveal melanoma. In conclusion, these data provide the first evidence that sigma receptors may represent a "druggable" target to develop new chemotherapic agent for uveal melanoma.

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Historical perspectives and recent advances in small molecule ligands of selective/biased/multi-targeted μ/δ/κ opioid receptor (2019–2022)

He,

Su,

Zhao

et al. 2023

Bioorganic Chemistry

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Evaluation of N-substitution in 6,7-benzomorphan compounds

Cited by 36 publications

References 25 publications

Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists

Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists

Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

Historical perspectives and recent advances in small molecule ligands of selective/biased/multi-targeted μ/δ/κ opioid receptor (2019–2022)

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