Molecular Structure of Two Conformationally Restrained Fentanyl Analogues: cis- and trans-isomers of N-{3-Methyl-1-[2-(1,2,3,4-tetrahydro)naphthyl]-4-piperidinyl}-N-phenylpropanamide

Klein, Cheryl L.; Stevens, Edwin D.; Fifer, E. Kim; Borne, Ronald F.

doi:10.1002/jps.2600741103

Cited by 5 publications

(2 citation statements)

References 15 publications

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“…During nitrogen inversion, the trans conformation may hinder the piperidine ring more than the cis conformation but not enough to produce antagonism. 16 Proposition #5 The first 3 amino acid sequences of beta endorphin (l-try-gly-gly) and the active opioid dipeptide, l-tyr-pro, (as a result of a peptide turn and zwitterion bonding) form a virtual piperazine-like ring which is similar in size, shape and location to the heterocyclic rings of morphine, meperidine, and methadone…”

Section: Klein Et Al Studied Two Restrained Analogues Ofmentioning

confidence: 99%

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Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides

Goldberg

2010

Perspect Medicin Chem

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This paper presents a novel unified theory of the structure activity relationship of opioids and opioid peptides. It is hypothesized that a virtual or known heterocyclic ring exists in all opioids which have activity in humans, and this ring occupies relative to the aromatic ring of the drug, approximately the same plane in space as the piperidine ring of morphine. Since the rings of morphine are rigid, and the aromatic and piperidine rings are critical structural components for morphine’s analgesic properties, the rigid morphine molecule allows for approximations of the aromatic and heterocyclic relationships in subsequent drug models where bond rotations are common. This hypothesis and five propositions are supported by stereochemistry and experimental observations.Proposition #1 The structure of morphine provides a template. Proposition #2 Steric hindrance of some centric portion of the piperidine ring explains antagonist properties of naloxone, naltrexone and alvimopam. Proposition #3 Methadone has an active conformation which contains a virtual heterocyclic ring which explains its analgesic activity and racemic properties. Proposition #4 The piperidine ring of fentanyl can assume the morphine position under conditions of nitrogen inversion. Proposition #5 The first 3 amino acid sequences of beta endorphin (l-try-gly-gly) and the active opioid dipeptide, l-tyr-pro, (as a result of a peptide turn and zwitterion bonding) form a virtual piperazine-like ring which is similar in size, shape and location to the heterocyclic rings of morphine, meperidine, and methadone. Potential flaws in this theory are discussed.This theory could be important for future analgesic drug design.

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Section: Klein Et Al Studied Two Restrained Analogues Ofmentioning

confidence: 99%

“…During nitrogen inversion, the trans conformation may hinder the piperidine ring more than the cis conformation but not enough to produce antagonism. 16…”

Section: Rationale For Selection Of Opioids To Investigatementioning

confidence: 99%

Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides

Goldberg

2010

Perspect Medicin Chem

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Synthesis and x‐ray crystal structures of isonipecotinamide derivatives as reverse amide analogues of fentanyl

Borne

Gatchell

Klein

et al. 1990

Journal of Heterocyclic Chem

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Accurate prediction of terahertz spectra of molecular crystals of fentanyl and its analogs

Wang

Terracciano

Masunov

et al. 2021

Sci Rep

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Fentanyl is a potent synthetic opioid pain reliever with a high bioavailability that can be used as prescription anesthetic. Rapid identification via non-contact methods of both known and emerging opioid substances in the fentanyl family help identify the substances and enable rapid medical attention. We apply PBEh-3c method to identify vibrational normal modes from 0.01 to 3 THz in solid fentanyl and its selected analogs. The molecular structure of each fentanyl analog and unique arrangement of H-bonds and dispersion interactions significantly change crystal packing and is subsequently reflected in the THz spectrum. Further, the study of THz spectra of a series of stereoisomers shows that small changes in molecular structure results in distinct crystal packing and significantly alters THz spectra as well. We discuss spectral features of synthetic opioids with higher potency than conventional fentanyl such as ohmefentanyl and sufentanil and discover the pattern of THz spectra of fentanyl analogs.

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Molecular Structure of Two Conformationally Restrained Fentanyl Analogues: cis- and trans-isomers of N-{3-Methyl-1-[2-(1,2,3,4-tetrahydro)naphthyl]-4-piperidinyl}-N-phenylpropanamide

Cited by 5 publications

References 15 publications

Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides

Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides

Synthesis and x‐ray crystal structures of isonipecotinamide derivatives as reverse amide analogues of fentanyl

Accurate prediction of terahertz spectra of molecular crystals of fentanyl and its analogs

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