The Intriguing Effects of Substituents in the <i>N</i>-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
Affiliations
Meining Wang
Department of Health and Human Services, 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, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA
Thomas C. Irvin
Department of Health and Human Services, 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, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA
Christine A. Herdman
Department of Health and Human Services, 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, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA
Ramsey D. Hanna
Department of Health and Human Services, 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, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA
Sergio A. Hassan
Department of Health and Human Services, Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA
Yong-Sok Lee
Department of Health and Human Services, Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA
Sophia Kaska
Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045-7582, USA
Rachel Saylor Crowley
Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045-7582, USA
Thomas E. Prisinzano
Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045-7582, USA
Sarah L. Withey
Behavioral Biology Program, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
Carol A. Paronis
Behavioral Biology Program, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
Jack Bergman
Behavioral Biology Program, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
Saadet Inan
Center for Substance Abuse Research, Lewis Katz School of Medicine of Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USA
Ellen B. Geller
Center for Substance Abuse Research, Lewis Katz School of Medicine of Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USA
Martin W. Adler
Center for Substance Abuse Research, Lewis Katz School of Medicine of Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USA
Theresa A. Kopajtic
Department of Health and Human Services, Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
Jonathan L. Katz
Department of Health and Human Services, Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
Aaron M. Chadderdon
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
John R. Traynor
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Arthur E. Jacobson
Department of Health and Human Services, 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, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA
Kenner C. Rice
Department of Health and Human Services, 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, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA
(−)-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-chloro-phenethynorhydromorphone ((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 side-effects 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.
