Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

Abstract

Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the μOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

Novel Opioids: Systematic Web Crawling Within the e-Psychonauts’ Scenario

“…Although present findings do not necessarily confirm in any possible way these substances' levels of use, they can still reflect the attention given by psychonauts to these drugs and help in explaining aspects of the current "opioid epidemic" (Kakko et al, 2019;Zhao, 2019). A few fentanyl analogs have been mentioned in the literature (Suzuki and El-Haddad, 2017;Zawilska, 2017;Misailidi et al, 2018;Lipiński et al, 2019), especially in terms of the acute clinical toxicity issues relating to their intake (Abdulrahim and Bowden-Jones, 2018). Vulnerable subjects can access online a large number of these substances (Suzuki and El-Haddad, 2017), without even being aware of what they are taking exactly (Ciccarone et al, 2017;Bardwell et al, 2019;McLean et al, 2019;Stein et al, 2019).…”

Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

“…Further, Phe3 in 1 and Phe4 in DAMGO are situated in the same S2 site. S2 is also occupied by phenyl rings of small molecular agonist BU72 in 5 C1 M [12] crystal structure ( Figure S18) or of fentanyl [32,33] according to molecular modeling ( Figure S19). The analogues of 1 were predicted to bind in orientations largely similar to that of the parent compound.…”

Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus

“…The main features of this binding mode are (1) the canonical ionic interaction of the protonated Tyr 1 amine with D147, (2) the location of the Tyr 1 phenol group close to H297, and (3) the position of the Phe 4 in a hydrophobic subsite made of side chains of several residues belonging to transmembrane helix 3 (TM3) and extracellular loops 1 and 2 (ECL1 and ECL2). The first and the third features correspond to analogous elements of the binding modes of small molecular MOR agonist BU72 (as found in crystal structure 5C1M [ 46 ]) or fentanyl (as found by modelling [ 42 , 47 ]).…”

“…In general, the most potent MOR ligands reported here (1c and 1d) have similarly high affinity as typical reference opioids, be they peptides (like biphalin, MOR IC 50 = 1.4 nM [33]) or non-peptides (like morphine, IC 50 = 4.02 nM [42]).…”