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

Molecules. 2022 Sep 30;27(19):6455. doi: 10.3390/molecules27196455.

Authors

Affiliations

¹ Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892, USA.
² Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, KY 40536, USA.
³ Computational Chemistry and Molecular Biophysics Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 333 Cassell Drive, Baltimore, MD 21224, USA.
⁴ McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
⁵ Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA 23298, USA.
⁶ Naval Research Laboratory, Center for Biomolecular Science and Engineering, Washington, DC 20375, USA.

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.

MeSH terms

Animals
CHO Cells
Colforsin
Cricetinae
Ligands
Mice
Morphine / pharmacology
Naltrexone*
Receptors, Opioid / metabolism
Receptors, Opioid, delta / metabolism
Receptors, Opioid, mu / metabolism
Respiratory Insufficiency*

Substances

Ligands
Receptors, Opioid
Receptors, Opioid, delta
Receptors, Opioid, mu
Colforsin
Naltrexone
Morphine

Abstract

MeSH terms

Substances

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