Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder
The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fa...
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2024
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| _version_ | 1852024701691363328 |
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| author | Boshi Huang (3080169) |
| author2 | Hongguang Ma (5105198) Piyusha P. Pagare (4433698) Mengchu Li (8108468) Rolando E. Mendez (12210748) James C. Gillespie (12210745) Justin L. Poklis (4117759) Matthew S. Halquist (1331493) David L. Stevens (1878574) William L. Dewey (306219) Dana E. Selley (1448944) Yan Zhang (8098) |
| author2_role | author author author author author author author author author author author |
| author_facet | Boshi Huang (3080169) Hongguang Ma (5105198) Piyusha P. Pagare (4433698) Mengchu Li (8108468) Rolando E. Mendez (12210748) James C. Gillespie (12210745) Justin L. Poklis (4117759) Matthew S. Halquist (1331493) David L. Stevens (1878574) William L. Dewey (306219) Dana E. Selley (1448944) Yan Zhang (8098) |
| author_role | author |
| dc.creator.none.fl_str_mv | Boshi Huang (3080169) Hongguang Ma (5105198) Piyusha P. Pagare (4433698) Mengchu Li (8108468) Rolando E. Mendez (12210748) James C. Gillespie (12210745) Justin L. Poklis (4117759) Matthew S. Halquist (1331493) David L. Stevens (1878574) William L. Dewey (306219) Dana E. Selley (1448944) Yan Zhang (8098) |
| dc.date.none.fl_str_mv | 2024-12-05T13:23:45Z |
| dc.identifier.none.fl_str_mv | 10.1021/acsptsci.4c00593.s002 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/Discovery_of_6_-Thiazolylcarboxamidonaltrexamine_Derivative_NTZ_as_a_Potent_and_Central_Nervous_System_Penetrant_Opioid_Receptor_Modulator_with_Drug-like_Properties_for_Potential_Treatment_of_Opioid_Use_Disorder/27968559 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biochemistry Medicine Genetics Neuroscience Pharmacology Biotechnology Immunology Cancer Science Policy Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified previous efforts led alleviating withdrawal symptoms 16 new analogs opioid use disorder favorable admet profile several key drug ntz shows promise like properties suggested lead compound designated 6 </ b like properties vivo </ potential lead opioid domain favorable drug thiophene ring thiazolylcarboxamidonaltrexamine derivative taken together potential treatment nitrogen atom cns permeability antagonistic effect activity cliff |
| dc.title.none.fl_str_mv | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound <b>6</b> (NTZ) exhibited improved opioid receptor selectivity, enhanced <i>in vivo</i> antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder. |
| eu_rights_str_mv | openAccess |
| id | Manara_75203f900343ef330cf2d804637d94de |
| identifier_str_mv | 10.1021/acsptsci.4c00593.s002 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/27968559 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use DisorderBoshi Huang (3080169)Hongguang Ma (5105198)Piyusha P. Pagare (4433698)Mengchu Li (8108468)Rolando E. Mendez (12210748)James C. Gillespie (12210745)Justin L. Poklis (4117759)Matthew S. Halquist (1331493)David L. Stevens (1878574)William L. Dewey (306219)Dana E. Selley (1448944)Yan Zhang (8098)BiochemistryMedicineGeneticsNeurosciencePharmacologyBiotechnologyImmunologyCancerScience PolicyBiological Sciences not elsewhere classifiedChemical Sciences not elsewhere classifiedprevious efforts ledalleviating withdrawal symptoms16 new analogsopioid use disorderfavorable admet profileseveral key drugntz shows promiselike properties suggestedlead compound designated6 </ blike propertiesvivo </potential leadopioid domainfavorable drugthiophene ringthiazolylcarboxamidonaltrexamine derivativetaken togetherpotential treatmentnitrogen atomcns permeabilityantagonistic effectactivity cliffThe development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound <b>6</b> (NTZ) exhibited improved opioid receptor selectivity, enhanced <i>in vivo</i> antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.2024-12-05T13:23:45ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acsptsci.4c00593.s002https://figshare.com/articles/dataset/Discovery_of_6_-Thiazolylcarboxamidonaltrexamine_Derivative_NTZ_as_a_Potent_and_Central_Nervous_System_Penetrant_Opioid_Receptor_Modulator_with_Drug-like_Properties_for_Potential_Treatment_of_Opioid_Use_Disorder/27968559CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/279685592024-12-05T13:23:45Z |
| spellingShingle | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder Boshi Huang (3080169) Biochemistry Medicine Genetics Neuroscience Pharmacology Biotechnology Immunology Cancer Science Policy Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified previous efforts led alleviating withdrawal symptoms 16 new analogs opioid use disorder favorable admet profile several key drug ntz shows promise like properties suggested lead compound designated 6 </ b like properties vivo </ potential lead opioid domain favorable drug thiophene ring thiazolylcarboxamidonaltrexamine derivative taken together potential treatment nitrogen atom cns permeability antagonistic effect activity cliff |
| status_str | publishedVersion |
| title | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder |
| title_full | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder |
| title_fullStr | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder |
| title_full_unstemmed | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder |
| title_short | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder |
| title_sort | Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder |
| topic | Biochemistry Medicine Genetics Neuroscience Pharmacology Biotechnology Immunology Cancer Science Policy Biological Sciences not elsewhere classified Chemical Sciences not elsewhere classified previous efforts led alleviating withdrawal symptoms 16 new analogs opioid use disorder favorable admet profile several key drug ntz shows promise like properties suggested lead compound designated 6 </ b like properties vivo </ potential lead opioid domain favorable drug thiophene ring thiazolylcarboxamidonaltrexamine derivative taken together potential treatment nitrogen atom cns permeability antagonistic effect activity cliff |