Journal:PMC:1

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 .

An argument that a pharmacologically active methadone conformation includes a 'virtual heterocyclic ring' is based on the following assumptions:

. The (colored in lime). According to Pauling, the N-H-O bond is near linear. Therefore, the virtual ring has characteristics of a 6 member nitrogen containing ring which can be shown to be positioned in a plane similar to the (also colored in lime). The formation of the heterocyclic ring positions a methyl group connected to the chiral carbon which has steric influences on activity. and the medication has minimal analgesic activity, but in the and substantial analgesic effects. Similar to the steric blocking effects observed with naloxone and naltrexone, these .

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 β-endorphin (l-Tyr-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.

However, many apparently dissimilar, di, tri, tetra, penta, and polypeptides are known to have opioid activity, the smallest being l-Tyr-Pro. Within the peptide turn of This piperazine-like ring of Tyr-Gly-Gly and piperidine ring of morphine have similar conformations. Tyr-Pro is the minimal length peptide which has been shown to possess opioid activity.

Conclusion. A unified theory based on the stereochemistry of a common aromatic-heterocyclic relationship in opioid

and opioid peptides is presented. This theory is supported by five propositions which include experimental data derived from the literature and stereochemical observations from the author’s perspective. Some of the support for the propositions explains new relationships about steric hindrance and optical activity of opioids. This theory could be important for future analgesic drug design.