The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments

Meining Wang; Thomas C. Irvin; Christine A. Herdman; Ramsey D. Hanna; Sergio A. Hassan; Yong Sok Lee; Sophia Kaska; Rachel Saylor Crowley; Thomas E. Prisinzano; Sarah L. Withey; Carol A. Paronis; Jack Bergman; Saadet Inan; Ellen B. Geller; Martin W. Adler; Theresa A. Kopajtic; Jonathan L. Katz; Aaron M. Chadderdon; John R. Traynor; Arthur E. Jacobson; Kenner C. Rice

doi:10.3390/molecules25112640

The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments

Meining Wang, Thomas C. Irvin, Christine A. Herdman, Ramsey D. Hanna, Sergio A. Hassan, Yong Sok Lee, Sophia Kaska, Rachel Saylor Crowley, Thomas E. Prisinzano, Sarah L. Withey, Carol A. Paronis, Jack Bergman, Saadet Inan, Ellen B. Geller, Martin W. Adler, Theresa A. Kopajtic, Jonathan L. Katz, Aaron M. Chadderdon, John R. Traynor, Arthur E. JacobsonKenner C. Rice

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

(-)-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.

Original language	English
Article number	2640
Journal	Molecules
Volume	25
Issue number	11
DOIs	https://doi.org/10.3390/molecules25112640
State	Published - Jun 2020

Bibliographical note

Funding Information:
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 Information:
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.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

(-)-N-phenethylnorhydromorphone analogs
Bias factor
Bifunctional ligands
Forskolin-induced cAMP accumulation assays
MOR and DOR agonists
Opioid
Respiratory depression
[35S]GTPgammaS assay
β-arrestin recruitment assays

ASJC Scopus subject areas

Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Pharmaceutical Science
Drug Discovery
Physical and Theoretical Chemistry
Organic Chemistry

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10.3390/molecules25112640

Cite this

Wang, M., Irvin, T. C., Herdman, C. A., Hanna, R. D., Hassan, S. A., Lee, Y. S., Kaska, S., Crowley, R. S., Prisinzano, T. E., Withey, S. L., Paronis, C. A., Bergman, J., Inan, S., Geller, E. B., Adler, M. W., Kopajtic, T. A., Katz, J. L., Chadderdon, A. M., Traynor, J. R., ... Rice, K. C. (2020). The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments. Molecules, 25(11), [2640]. https://doi.org/10.3390/molecules25112640

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title = "The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of {"}tail wags dog{"} experiments",

abstract = "(-)-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.",

keywords = "(-)-N-phenethylnorhydromorphone analogs, Bias factor, Bifunctional ligands, Forskolin-induced cAMP accumulation assays, MOR and DOR agonists, Opioid, Respiratory depression, [35S]GTPgammaS assay, β-arrestin recruitment assays",

author = "Meining Wang and Irvin, {Thomas C.} and Herdman, {Christine A.} and Hanna, {Ramsey D.} and Hassan, {Sergio A.} and Lee, {Yong Sok} and Sophia Kaska and Crowley, {Rachel Saylor} and Prisinzano, {Thomas E.} and Withey, {Sarah L.} and Paronis, {Carol A.} and Jack Bergman and Saadet Inan and Geller, {Ellen B.} and Adler, {Martin W.} and Kopajtic, {Theresa A.} and Katz, {Jonathan L.} and Chadderdon, {Aaron M.} and Traynor, {John R.} and Jacobson, {Arthur E.} and Rice, {Kenner C.}",

note = "Funding Information: 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 Information: 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. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = jun,

doi = "10.3390/molecules25112640",

language = "English",

volume = "25",

number = "11",

}

Wang, M, Irvin, TC, Herdman, CA, Hanna, RD, Hassan, SA, Lee, YS, Kaska, S, Crowley, RS, Prisinzano, TE, Withey, SL, Paronis, CA, Bergman, J, Inan, S, Geller, EB, Adler, MW, Kopajtic, TA, Katz, JL, Chadderdon, AM, Traynor, JR, Jacobson, AE & Rice, KC 2020, 'The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments', Molecules, vol. 25, no. 11, 2640. https://doi.org/10.3390/molecules25112640

TY - JOUR

T1 - The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone

T2 - A bifunctional opioid from a set of "tail wags dog" experiments

AU - Wang, Meining

AU - Irvin, Thomas C.

AU - Herdman, Christine A.

AU - Hanna, Ramsey D.

AU - Hassan, Sergio A.

AU - Lee, Yong Sok

AU - Kaska, Sophia

AU - Crowley, Rachel Saylor

AU - Prisinzano, Thomas E.

AU - Withey, Sarah L.

AU - Paronis, Carol A.

AU - Bergman, Jack

AU - Inan, Saadet

AU - Geller, Ellen B.

AU - Adler, Martin W.

AU - Kopajtic, Theresa A.

AU - Katz, Jonathan L.

AU - Chadderdon, Aaron M.

AU - Traynor, John R.

AU - Jacobson, Arthur E.

AU - Rice, Kenner C.

N1 - Funding Information: 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 Information: 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. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/6

Y1 - 2020/6

N2 - (-)-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.

AB - (-)-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.

KW - (-)-N-phenethylnorhydromorphone analogs

KW - Bias factor

KW - Bifunctional ligands

KW - Forskolin-induced cAMP accumulation assays

KW - MOR and DOR agonists

KW - Opioid

KW - Respiratory depression

KW - [35S]GTPgammaS assay

KW - β-arrestin recruitment assays

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U2 - 10.3390/molecules25112640

DO - 10.3390/molecules25112640

M3 - Article

C2 - 32517185

AN - SCOPUS:85086355472

VL - 25

IS - 11

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ER -

The intriguing effects of substituents in the N-phenethyl moiety of norhydromorphone: A bifunctional opioid from a set of "tail wags dog" experiments

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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