Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain
Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alterna...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-08-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/16/5135 |
| _version_ | 1797443193487228928 |
|---|---|
| author | Rita Turnaturi Santina Chiechio Lorella Pasquinucci Salvatore Spoto Giuliana Costanzo Maria Dichiara Silvia Piana Margherita Grasso Emanuele Amata Agostino Marrazzo Carmela Parenti |
| author_facet | Rita Turnaturi Santina Chiechio Lorella Pasquinucci Salvatore Spoto Giuliana Costanzo Maria Dichiara Silvia Piana Margherita Grasso Emanuele Amata Agostino Marrazzo Carmela Parenti |
| author_sort | Rita Turnaturi |
| collection | DOAJ |
| description | Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σ<sub>1</sub>R) antagonism, could be an opioid adjuvant strategy. The in vitro σ<sub>1</sub>R and σ<sub>2</sub>R profiles of previous synthesized MOR/DOR agonists (−)-2<i>R</i>/<i>S</i>-LP2 (<b>1</b>), (−)-2<i>R</i>-LP2 (<b>2</b>), and (−)-2<i>S</i>-LP2 (<b>3</b>) were assayed. To investigate the pivotal role of <i>N</i>-normetazocine stereochemistry, we also synthesized the (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), (+)-2<i>R</i>-LP2 (<b>8</b>), and (+)-2<i>S</i>-LP2 (<b>9</b>) compounds. (−)-2<i>R</i>/<i>S</i>-LP2 (<b>1</b>), (−)-2<i>R</i>-LP2 (<b>2</b>), and (−)-2<i>S</i>-LP2 (<b>3</b>) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), (+)-2<i>R</i>-LP2 (<b>8</b>), and (+)-2<i>S</i>-LP2 (<b>9</b>) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (−)-2<i>S</i>-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed <i>N</i>-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin. |
| first_indexed | 2024-03-09T12:52:29Z |
| format | Article |
| id | doaj.art-fa89ceaf72aa4b489cc7b67a2f3fc901 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T12:52:29Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-fa89ceaf72aa4b489cc7b67a2f3fc9012023-11-30T22:04:30ZengMDPI AGMolecules1420-30492022-08-012716513510.3390/molecules27165135Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory PainRita Turnaturi0Santina Chiechio1Lorella Pasquinucci2Salvatore Spoto3Giuliana Costanzo4Maria Dichiara5Silvia Piana6Margherita Grasso7Emanuele Amata8Agostino Marrazzo9Carmela Parenti10Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug and Health Sciences, Section of Pharmacology and Toxicology, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug and Health Sciences, Section of Pharmacology and Toxicology, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, 95123 Catania, ItalyDepartment of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyOasi Research Institute—IRCCS, 94018 Troina, ItalyDepartment of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyDepartment of Drug and Health Sciences, Section of Pharmacology and Toxicology, University of Catania, Viale A. Doria 6, 95125 Catania, ItalyAlthough opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σ<sub>1</sub>R) antagonism, could be an opioid adjuvant strategy. The in vitro σ<sub>1</sub>R and σ<sub>2</sub>R profiles of previous synthesized MOR/DOR agonists (−)-2<i>R</i>/<i>S</i>-LP2 (<b>1</b>), (−)-2<i>R</i>-LP2 (<b>2</b>), and (−)-2<i>S</i>-LP2 (<b>3</b>) were assayed. To investigate the pivotal role of <i>N</i>-normetazocine stereochemistry, we also synthesized the (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), (+)-2<i>R</i>-LP2 (<b>8</b>), and (+)-2<i>S</i>-LP2 (<b>9</b>) compounds. (−)-2<i>R</i>/<i>S</i>-LP2 (<b>1</b>), (−)-2<i>R</i>-LP2 (<b>2</b>), and (−)-2<i>S</i>-LP2 (<b>3</b>) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), (+)-2<i>R</i>-LP2 (<b>8</b>), and (+)-2<i>S</i>-LP2 (<b>9</b>) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (−)-2<i>S</i>-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed <i>N</i>-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.https://www.mdpi.com/1420-3049/27/16/5135multitarget drugsMOR/DOR agonistsPRE-084formalin test |
| spellingShingle | Rita Turnaturi Santina Chiechio Lorella Pasquinucci Salvatore Spoto Giuliana Costanzo Maria Dichiara Silvia Piana Margherita Grasso Emanuele Amata Agostino Marrazzo Carmela Parenti Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain Molecules multitarget drugs MOR/DOR agonists PRE-084 formalin test |
| title | Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain |
| title_full | Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain |
| title_fullStr | Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain |
| title_full_unstemmed | Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain |
| title_short | Novel <i>N</i>-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain |
| title_sort | novel i n i normetazocine derivatives with opioid agonist sigma 1 receptor antagonist profile as potential analgesics in inflammatory pain |
| topic | multitarget drugs MOR/DOR agonists PRE-084 formalin test |
| url | https://www.mdpi.com/1420-3049/27/16/5135 |
| work_keys_str_mv | AT ritaturnaturi novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT santinachiechio novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT lorellapasquinucci novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT salvatorespoto novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT giulianacostanzo novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT mariadichiara novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT silviapiana novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT margheritagrasso novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT emanueleamata novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT agostinomarrazzo novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain AT carmelaparenti novelininormetazocinederivativeswithopioidagonistsigma1receptorantagonistprofileaspotentialanalgesicsininflammatorypain |