Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides
Joel S. Goldberg[1]
Molecular Tour
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.
The morphine rings are nearly
rigid with little rotational movement and therefore can be considered a template. The aromatic ring (A) and colored in lime) are essential for analgesic activity. (in yellow). If the (in cyan) is also eliminated, the molecule has limited activity as the position of the heterocyclic ring is significantly less rigid with more degrees of freedom of movement. The plane of the heterocyclic ring is defined by two vectors originating from the plane of the aromatic ring and the between two points on each plane. (colored in orange and lime, respectively).
Proposition #2. Steric hinderance of some centric portion of the piperidine ring explains antagonist properties of naloxone, naltrexone and alvimopam.
in Naloxone. is more antagonistic than Naloxone. In humans, (in yellow).
Proposition #3. Methadone has an active conformation which contains a virtual heterocyclic ring which explains its
analgesic activity and .
