Resumen
(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). "Body"and "tail"interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address"can be considered the "body"of the hydromorphone molecule and the "message"delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chlorophenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro- 1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer sideeffects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.
| Idioma original | English |
|---|---|
| Número de artículo | 2640 |
| Publicación | Molecules |
| Volumen | 25 |
| N.º | 11 |
| DOI | |
| Estado | Published - jun 2020 |
Nota bibliográfica
Publisher Copyright:© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Financiación
The work of SI: EBG, ad MWA was supported by NIDA grant P30 DA13429. The work of JRT was supported by NIDA grant DA039997. The work of SK, RSC and TEP was supported by NIDA grant DA018151. The work of SLW, CAP, and JB was supported by NIDA grants DA035857 and DA047574.The work of MW, TCI, CAH, AEJ and KCR was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. The work of TAK and JLK was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse. The work of SAH and YSL was supported by the NIH Intramural Research Program through the Center for Information Technology. The computational studies utilized PC/LINUX clusters at the Center for Molecular Modeling of the NIH (http://cmm.cit.nih.gov) and the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). The work of TAK and JLK was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse. We thank the NIDA Drug Supply for providing compounds used in the forskolin-induced cAMP assays. We also thank Dr. John Lloyd and Noel Whittaker (Mass Spectrometry Facility, NIDDK) for the mass spectral data, and S. Steven Negus (Dept. of Pharmacology and Toxicology. Virginia Commonwealth University, Richmond VA) for helpful discussions about the possible pharmacological effects of compounds with MOR and DOR agonist activity Funding: The work of SI: EBG, ad MWA was supported by NIDA grant P30 DA13429. The work of JRT was supported by NIDA grant DA039997. The work of SK, RSC and TEP was supported by NIDA grant DA018151. The work of SLW, CAP, and JB was supported by NIDA grants DA035857 and DA047574.The work of MW, TCI, CAH, AEJ and KCR was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. The work of TAK and JLK was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse. The work of SAH and YSL was supported by the NIH Intramural Research Program through the Center for Information Technology. The computational studies utilized PC/LINUX clusters at the Center for Molecular Modeling of the NIH (http://cmm.cit.nih.gov) and the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). The work of TAK and JLK was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse. We thank the NIDA Drug Supply for providing compounds used in the forskolin‐induced cAMP assays. We also thank Dr. John Lloyd and Noel Whittaker (Mass Spectrometry Facility, NIDDK) for the mass spectral data, and S. Steven Negus (Dept. of Pharmacology and Toxicology. Virginia Commonwealth University, Richmond VA) for helpful discussions about the possible pharmacological effects of compounds with MOR and DOR agonist activity.
| Financiadores | Número del financiador |
|---|---|
| John Lloyd and Noel Whittaker | |
| National Institutes of Health (NIH) | |
| National Institute on Drug Abuse | DA035857, P30DA013429, DA018151, DA039997 |
| National Institute on Drug Abuse | |
| National Institute on Alcohol Abuse and Alcoholism | |
| National Institute of Diabetes and Digestive and Kidney Diseases | |
| Center for Information Technology | |
| Virginia Commonwealth University | |
| British Mass Spectrometry Society |
ASJC Scopus subject areas
- Analytical Chemistry
- Chemistry (miscellaneous)
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery
- Physical and Theoretical Chemistry
- Organic Chemistry