Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists
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 a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-03-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/3/677 |
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| author | Rita Turnaturi Carmela Parenti Orazio Prezzavento Agostino Marrazzo Paschalina Pallaki Zafiroula Georgoussi Emanuele Amata Lorella Pasquinucci |
| author_facet | Rita Turnaturi Carmela Parenti Orazio Prezzavento Agostino Marrazzo Paschalina Pallaki Zafiroula Georgoussi Emanuele Amata Lorella Pasquinucci |
| author_sort | Rita Turnaturi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T20:39:14Z |
| format | Article |
| id | doaj.art-534692b1e0004998bda30f1bf543247b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-12T20:39:14Z |
| publishDate | 2018-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-534692b1e0004998bda30f1bf543247b2022-12-22T03:17:29ZengMDPI AGMolecules1420-30492018-03-0123367710.3390/molecules23030677molecules23030677Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR AgonistsRita Turnaturi0Carmela Parenti1Orazio Prezzavento2Agostino Marrazzo3Paschalina Pallaki4Zafiroula Georgoussi5Emanuele Amata6Lorella Pasquinucci7Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyLaboratory of Cellular Signaling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos” Agia Paraskevi-Attikis, 15310 Athens, GreeceLaboratory of Cellular Signaling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos” Agia Paraskevi-Attikis, 15310 Athens, GreeceDepartment of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyThe 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.http://www.mdpi.com/1420-3049/23/3/6776,7-benzomorphan derivativesMOR agonistpainradioligand competitive bindingcAMP accumulation assaytail-flick test |
| spellingShingle | Rita Turnaturi Carmela Parenti Orazio Prezzavento Agostino Marrazzo Paschalina Pallaki Zafiroula Georgoussi Emanuele Amata Lorella Pasquinucci Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists Molecules 6,7-benzomorphan derivatives MOR agonist pain radioligand competitive binding cAMP accumulation assay tail-flick test |
| title | Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists |
| title_full | Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists |
| title_fullStr | Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists |
| title_full_unstemmed | Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists |
| title_short | Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists |
| title_sort | synthesis and structure activity relationships of lp1 derivatives n methyl n phenylethylamino analogues as novel mor agonists |
| topic | 6,7-benzomorphan derivatives MOR agonist pain radioligand competitive binding cAMP accumulation assay tail-flick test |
| url | http://www.mdpi.com/1420-3049/23/3/677 |
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