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.

Low Molecular Weight Opioid Peptide Esters Could be Developed as a New Class of Analgesics

“…27,28 The structure of tyr-pro and try-gly could assume an active conformation of an aromatic and virtual hetereocylic (piperazine like) ring which in theory may be related to analgesia. 16 Ethanol, cholesterol and 3-glucose are possible conjugates which can be used to form the lead OPE. OPE of ethanol are particularly attractive because of the structural resemblance to etomidate which rapidly enters the CNS after intravenous administration (Fig.…”

“… 27 , 28 The structure of tyr-pro and try-gly could assume an active conformation of an aromatic and virtual hetereocylic (piperazine like) ring which in theory may be related to analgesia. 16 …”

“… 15 The OP may bind more efficiently than opiates to the mu receptor because the structure of the OP is different and lacks the piperidine ring found in morphine and its derivatives. 16 (3) Similar to many hormones, OP couple to G protein receptors for activity. After the onset of clinical symptoms, tolerance to the hypersecretory effects of other endogenous hormones that occur in disease states such as Cushing’s syndrome and disease, pheochromocytoma, and carcinoid syndrome is exceedingly rare, a mechanism of action that could be shared with OP.…”

Some Mechanistic Aspects on Fmoc Solid Phase Peptide Synthesis

“…Peptides are widespread molecules in nature, and they have several biological activities such as antimicrobial (Hancock and Scott 2000;Zasloff 2002), antithrombotic (Menezes et al 2011), opioid (Goldberg 2010), antioxidant (Zhang et al 2011) and so on. Therefore, peptides are important to the environment in which they operate and also as an object for the development of new drugs (Brogden 2005).…”

Identificação e caracterização de peptídeos opioides presentes na fração proteica dos grãos de Coffea arabica

“…Devido aos principais efeitos indesejáveis que a morfina pode provocar, tais como a diminuição da motilidade gastrointestinal, a depressão respiratória e a resistência, existe o interesse no estudo de novos compostos opioides que possam interagir com alvos específicos, produzindo poucos efeitos indesejáveis, baixo risco de resistência e com potência elevada (Goldberg, 2010;Gorzo et al, 2010).…”