Abstract
Few opioid ligands binding to the three classic opioid receptor subtypes, mu, kappa and delta, have high affinity at the fourth opioid receptor, the nociceptin/orphanin FQ receptor (NOP). We recently reported the discovery of AT-076 (1), (R)-7-hydroxy-N-((S)-1-(4-(3-hydroxyphenyl)piperidin-1-yl)-3-methylbutan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, a pan antagonist with nanomolar affinity for all four subtypes. Since AT-076 binds with high affinity at all four subtypes, we conducted a structure-activity relationship (SAR) study to probe ligand recognition features important for pan opioid receptor activity, using chemical modifications of key pharmacophoric groups. SAR analysis of the resulting analogs suggests that for the NOP receptor, the entire AT-076 scaffold is crucial for high binding affinity, but the binding mode is likely different from that of NOP antagonists C-24 and SB-612111 bound in the NOP crystal structure. On the other hand, modifications of the 3-hydroxyphenyl pharmacophore, but not the 7-hydroxy Tic pharmacophore, are better tolerated at kappa and mu receptors and yield very high affinity multifunctional (e.g. 12) or highly selective (e.g. 16) kappa ligands. With the availability of the opioid receptor crystal structures, our SAR analysis of the common chemotype of AT-076 suggests rational approaches to modulate binding selectivity, enabling the design of multifunctional or selective opioid ligands from such scaffolds.
Highlights
Very few opioid ligands show promiscuous high-affinity binding to all four opioid receptor subtypes, mu, kappa, delta and the nociceptin opioid receptors (MOP, KOP, DOP, nociceptin/orphanin FQ receptor (NOP) respectively)
The nanomolar binding affinity of AT-076 to all four opioid receptors suggests that AT-076 possesses a chemotype that can bind with high affinity at all four opioid receptors and can function as a universal opioid scaffold
The highest-scoring docked orientation of AT-076 in the NOP binding pocket was similar to the binding orientations of crystallized NOP antagonists C-24 and SB-612111 in the NOP receptor, such that the aromatic moiety at the 4-position of the piperidine ring was oriented towards the intracellular end of the binding pocket, consisting of hydrophobic residues Met1343.36, Phe1353.37, Ile2195.42 and Val2836.55
Summary
Very few opioid ligands show promiscuous high-affinity binding to all four opioid receptor subtypes, mu, kappa, delta and the nociceptin opioid receptors (MOP, KOP, DOP, NOP respectively). Prior to the recent determination of the X-ray crystal structures of the four opioid receptors bound to their selective antagonist ligands, elegant structure-activity relationship (SAR) studies of opioid ligands, in conjunction with site-directed mutagenesis, provided seminal information on the similarities and differences in opioid receptor binding pockets and selectivity-enhancing pharmacophoric features of opioid ligands Using these approaches receptor-selective opioid ligands were designed from universal opioid scaffolds; for example, kappa-selective antagonist norbinaltorphimine (norBNI)[4,5] and delta-selective antagonist naltrindole (NTI)[6] were designed from the non-selective opioid antagonist naltrexone (Fig. 1), and the kappa-selective antagonist, 5′-guanidinylnaltrindole (GNTI) was designed from the delta-selective antagonist NTI7,8. The highest-scoring docked orientation of AT-076 in the NOP binding pocket was similar to the binding orientations of crystallized NOP antagonists C-24 and SB-612111 in the NOP receptor (shown in Fig. 2), such that the aromatic moiety at the 4-position of the piperidine ring (benzofuran ring in C-24, 2,6-dichlorophenyl in SB-612111, and 3-hydroxyphenyl in AT-076) was oriented towards the intracellular end of the binding pocket, consisting of hydrophobic residues Met1343.36, Phe1353.37, Ile2195.42 and Val2836.55
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