A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

Dana R. Chambers; Agnieszka Sulima; Dan Luo; Thomas E. Prisinzano; Alexander Goldberg; Bing Xie; Lei Shi; Carol A. Paronis; Jack Bergman; Nima Nassehi; Dana E. Selley; Gregory H. Imler; Arthur E. Jacobson; Kenner C. Rice

doi:10.3390/molecules27196455

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

Dana R. Chambers, Agnieszka Sulima, Dan Luo, Thomas E. Prisinzano, Alexander Goldberg, Bing Xie, Lei Shi, Carol A. Paronis, Jack Bergman, Nima Nassehi, Dana E. Selley, Gregory H. Imler, Arthur E. Jacobson, Kenner C. Rice

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

3 Scopus citations

Abstract

Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [³⁵S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.

Original language	English
Article number	6455
Journal	Molecules
Volume	27
Issue number	19
DOIs	https://doi.org/10.3390/molecules27196455
State	Published - Oct 2022

Bibliographical note

Funding Information:
The work of D.R.C., A.S., A.E.J. and K.C.R. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. The work of A.G., B.X. and L.S. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse (Z1A DA000606—L.S.). The work of D.E.S. and N.N. was supported by P30-DA033934 and T32-DA007024, and the work of C.A.P. and J.B. was funded by DA047574. This work was also supported in part by DA051377 (to T.E.P.) and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (T.E.P.). The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). NIH, DHHS.

Publisher Copyright:
© 2022 by the authors.

Keywords

DOR
KOR agonists and antagonists
MOR
N-phenethyl-2-azabicyclo [3.3.1] nonan-5-yl) phenols
active (6DDF) MOR crystal structures
diastereomeric C9-alkenyl 5-phenylmorphans
inactive (4DKL) MOR crystal structures
m-hydroxy-N-phenethyl-5-phenylmorphan
molecular modeling and simulation
respiratory depression

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/molecules27196455

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Chambers, D. R., Sulima, A., Luo, D., Prisinzano, T. E., Goldberg, A., Xie, B., Shi, L., Paronis, C. A., Bergman, J., Nassehi, N., Selley, D. E., Imler, G. H., Jacobson, A. E., & Rice, K. C. (2022). A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists. Molecules, 27(19), Article 6455. https://doi.org/10.3390/molecules27196455

@article{89e5ae264e5f44c3a0ab7641d4644cde,

title = "A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists",

abstract = "Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.",

keywords = "DOR, KOR agonists and antagonists, MOR, N-phenethyl-2-azabicyclo [3.3.1] nonan-5-yl) phenols, active (6DDF) MOR crystal structures, diastereomeric C9-alkenyl 5-phenylmorphans, inactive (4DKL) MOR crystal structures, m-hydroxy-N-phenethyl-5-phenylmorphan, molecular modeling and simulation, respiratory depression",

author = "Chambers, {Dana R.} and Agnieszka Sulima and Dan Luo and Prisinzano, {Thomas E.} and Alexander Goldberg and Bing Xie and Lei Shi and Paronis, {Carol A.} and Jack Bergman and Nima Nassehi and Selley, {Dana E.} and Imler, {Gregory H.} and Jacobson, {Arthur E.} and Rice, {Kenner C.}",

note = "Funding Information: The work of D.R.C., A.S., A.E.J. and K.C.R. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. The work of A.G., B.X. and L.S. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse (Z1A DA000606—L.S.). The work of D.E.S. and N.N. was supported by P30-DA033934 and T32-DA007024, and the work of C.A.P. and J.B. was funded by DA047574. This work was also supported in part by DA051377 (to T.E.P.) and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (T.E.P.). The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). NIH, DHHS. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = oct,

doi = "10.3390/molecules27196455",

language = "English",

volume = "27",

number = "19",

}

Chambers, DR, Sulima, A, Luo, D, Prisinzano, TE, Goldberg, A, Xie, B, Shi, L, Paronis, CA, Bergman, J, Nassehi, N, Selley, DE, Imler, GH, Jacobson, AE & Rice, KC 2022, 'A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists', Molecules, vol. 27, no. 19, 6455. https://doi.org/10.3390/molecules27196455

TY - JOUR

T1 - A Journey through Diastereomeric Space

T2 - The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

AU - Chambers, Dana R.

AU - Sulima, Agnieszka

AU - Luo, Dan

AU - Prisinzano, Thomas E.

AU - Goldberg, Alexander

AU - Xie, Bing

AU - Shi, Lei

AU - Paronis, Carol A.

AU - Bergman, Jack

AU - Nassehi, Nima

AU - Selley, Dana E.

AU - Imler, Gregory H.

AU - Jacobson, Arthur E.

AU - Rice, Kenner C.

N1 - Funding Information: The work of D.R.C., A.S., A.E.J. and K.C.R. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism. The work of A.G., B.X. and L.S. was supported by the NIH Intramural Research Program (IRP) of the National Institute on Drug Abuse (Z1A DA000606—L.S.). The work of D.E.S. and N.N. was supported by P30-DA033934 and T32-DA007024, and the work of C.A.P. and J.B. was funded by DA047574. This work was also supported in part by DA051377 (to T.E.P.) and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (T.E.P.). The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). NIH, DHHS. Publisher Copyright: © 2022 by the authors.

PY - 2022/10

Y1 - 2022/10

N2 - Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.

AB - Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.

KW - DOR

KW - KOR agonists and antagonists

KW - MOR

KW - N-phenethyl-2-azabicyclo [3.3.1] nonan-5-yl) phenols

KW - active (6DDF) MOR crystal structures

KW - diastereomeric C9-alkenyl 5-phenylmorphans

KW - inactive (4DKL) MOR crystal structures

KW - m-hydroxy-N-phenethyl-5-phenylmorphan

KW - molecular modeling and simulation

KW - respiratory depression

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U2 - 10.3390/molecules27196455

DO - 10.3390/molecules27196455

M3 - Article

C2 - 36234992

AN - SCOPUS:85139834159

SN - 1420-3049

VL - 27

JO - Molecules

JF - Molecules

IS - 19

M1 - 6455

ER -

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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