Stereochemical basis for a unified structure activity theory of aromatic and heterocyclic rings in selected opioids and opioid peptides.
Abstract
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.
Type
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https://hdl.handle.net/10161/19174Published Version (Please cite this version)
10.4137/pmc.s3898Publication Info
Goldberg, Joel S (2010). Stereochemical basis for a unified structure activity theory of aromatic and heterocyclic
rings in selected opioids and opioid peptides. Perspectives in medicinal chemistry, 4(4). pp. 1-10. 10.4137/pmc.s3898. Retrieved from https://hdl.handle.net/10161/19174.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Joel Steven Goldberg
Adjunct Professor in the Department of Anesthesiology

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