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.

Morphine consists of rings A, B, C, D, and E. The morphine rings are nearly rigid with little rotational movement and therefore can be considered a template. The aromatic ring (A) and heterocyclic ring incorporating nitrogen (piperidine ring (E), colored in lime) are essential for analgesic activity. The B and C rings can be eliminated with minimal loss of activity (in yellow). If the D ring (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 distance between two points on each plane. Meperidine is the simplest active opioid and is comprised of an aromatic ring and piperidine ring (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.

These steric effects are caused by the OH and allyl side chains which block more than a peripheral portion of the piperidine ring in Naloxone. Naltrexone with a bulkier side chain is more antagonistic than Naloxone. In humans, Alvimopam is an antagonist and there is significant hindrance of the piperidine ring by the second aromatic ring (in yellow).

Proposition #3. Methadone has an active conformation which contains a virtual heterocyclic ring which explains its analgesic activity and racemic properties.

Methadone has a unique structure compared to other opioids since it does not possess a heterocyclic ring. An argument that a pharmacologically active methadone conformation includes a 'virtual heterocyclic ring' is based on the following assumptions:

Methadone contains a ketone group which also exists in equilibrium as an enol tautomer. The OH in the enol tautomer can form an intramolecular H-bond with the tertiary nitrogen and produce a seven member heterocyclic ring (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 piperidine ring of morphine (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. In the chair conformation of the d isomer, the methyl group hinders the heterocyclic ring and the medication has minimal analgesic activity, but in the l isomer there is no ring hindrance and substantial analgesic effects. Similar to the steric blocking effects observed with naloxone and naltrexone, these steric effects explain why l-methadone is active and d-methadone is relatively inactive.

Proposition #4. The piperidine ring of Fentanyl can assume the morphine position under conditions of nitrogen inversion.

A rigid tertiary amine moiety of fentanyl limits conformational changes which would allow the piperidine ring to assume a position similar to that found in morphine unless nitrogen inversion exists.

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.

Tyr-Gly-Gly- is the N terminus amino acid sequence of beta-endorphin. 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 Tyr-Gly-Gly an ionic bond and virtual heterocyclic ring exists formed by the intramolecular zwitterion attraction of the negative carbonyl oxygen to the positively charged nitrogen of tyrosine. 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. Tyr-Pro can also form a H-bonded virtual ring and peptide turn which is consistent with this proposition.

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