Fentanyl Analogs: Structure-Activity-Relationship Study

Abstract

Fentanyl is the prototype of the 4-anilidopiperidine class of synthetic opioid analgesics. This study was aimed to review the structure-activity-relationship (SAR) of fentanyl analogs substituted in the position 3, or 4 of the piperidine ring. Pharmacological results show that the groups in position 3 of the piperidine ring, which are larger than methyl, severely reduce the analgesic potency compared to fentanyl. It is likely that the steric factor alone (i.e. voluminosity of the group and cis/trans isomerism), rather than the polarity and/or chemical reactivity, plays a crucial role in the analgesic potency of this series. Although the duration of action, in general, does not depend on the stereochemistry, longer action of the most potent 3-alkyl fentanyl analogs such as cis-3-methyl- and cis-3-ethyl fentanyl, is more likely influenced by pharmacodynamic, rather than pharmacokinetic variables. Also, it is possible that the introduction of a functional group such as 3-carbomethoxy reduces the duration of action by altering pharmacokinetic properties. SAR findings obtained by evaluating the neurotoxic effects of fentanyl analogs substituted in the position 3 of the piperidine ring parallel the SAR findings on analgesia in regard to potency and duration of action. This might suggest that similar receptors are involved in producing both antinociceptive and neurotoxic effects of these drugs. It appears that both the potency and the duration of action in the series of fentanyl analogs substituted in position 4 of the piperidine ring is influenced only by the steric requirement and not by the chemical nature of the substituent.

Misuse of Novel Synthetic Opioids: A Deadly New Trend

“…Among the major classes of μ-opioid receptor agonists, 4-anilidopiperidines (i.e., fentanyl analogs) have a prominent place in clinical usage because of their high potency, low cardiovascular toxicity, rapid onset and short duration of action (Vucković, 2009). These properties arise from their high lipophilicity which allows them to distribute rapidly across the blood-brain barrier (Williams et al, 2013).…”

“…These properties arise from their high lipophilicity which allows them to distribute rapidly across the blood-brain barrier (Williams et al, 2013). Fentanyl is the prototypic 4-anilidopiperidine, and a large number of fentanyl analogs have been synthesized since the 1960s (Vucković, 2009). The same properties which give fentanyl its therapeutic attributes can lead to life-threatening adverse effects when the drug is consumed illicitly, especially at high doses.…”

“…At present, there are no data available on possible fatalities associated with valerylfentanyl, or descriptions of pharmacological effects in humans or animals. Extrapolating from known SAR for fentanyl compounds, which show analgesic potency decreases with increasing length of carboxamide substituents, it can be inferred that valerylfentanyl would be less potent than butyrylfentanyl (Vucković et al, 2009). …”

Neurotoxicity evaluation of fentanyl analogs in rats

“…The most common approach in searching for novel drugs is structural modification of the well known compounds (Mi}ovi} et al, 2000;Ivanovi} et al, 2004a;Ivanovi} et al, 2004b;Vu~kovi} et al, 2009). Among the important properties of the opioids that can be altered by structural modification are their affinities for various types of opioid receptors, activities as agonists versus antagonists, lipid solubilities, and their susceptibility/resistance to metabolic breakdown (Feldman et al, 1991;Scholz et al, 1996;Ananthan, 2006).…”

Synthesis of novel norsufentanil analogs via a four‐component Ugi reaction and in vivo, docking, and QSAR studies of their analgesic activity

“…Some investigations were performed to add heterocyclic rings to different parts of the lead compound, and their pharmacological properties were studied . In some researches, the influence of the three‐dimensional structure of these molecules in interaction with opioid receptors was investigated …”