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. 2012 Nov;80(5):763-70.
doi: 10.1111/cbdd.12014. Epub 2012 Sep 12.

Modulation of opioid receptor ligand affinity and efficacy using active and inactive state receptor models

Jessica P Anand  1 , Lauren C Purington, Irina D Pogozheva, John R Traynor, Henry I Mosberg
Affiliations

Modulation of opioid receptor ligand affinity and efficacy using active and inactive state receptor models

Jessica P Anand et al. Chem Biol Drug Des. 2012 Nov.

Abstract

Mu opioid receptor (MOR) agonists are widely used for the treatment of pain; however, chronic use results in the development of tolerance and dependence. It has been demonstrated that coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist maintains the analgesia associated with MOR agonists, but with reduced negative side-effects. Using our newly refined opioid receptor models for structure-based ligand design, we have synthesized several pentapeptides with tailored affinity and efficacy profiles. In particular, we have obtained pentapeptides 8, Tyr-c(S-S)[DCys-1Nal-Nle-Cys]NH(2), and 12, Tyr-c(S-S)[DCys-1Nal-Nle-Cys]OH, which demonstrates high affinity and full agonist behavior at MOR, high affinity but very low efficacy for DOR, and minimal affinity for the kappa opioid receptor (KOR). Functional properties of these peptides as MOR agonists/DOR antagonists lacking undesired KOR activity make them promising candidates for future in vivo studies of MOR/DOR interactions. Subtle structural variation of 12, by substituting D-Cys(5) for L-Cys(5), generated analog 13, which maintains low nanomolar MOR and DOR affinity, but which displays no efficacy at either receptor. These results demonstrate the power and utility of accurate receptor models for structure-based ligand design, as well as the profound sensitivity of ligand function on its structure.

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Figures

Figure 1
Figure 1
Modeling of peptide 1 (Tyr-c(S-S)[DCys-Phe-Phe-Cys]NH2) docked in the KOR active state model. Highlighted is the π-π interaction between Phe4 of 1 with Tyr219 of KOR (shown by dots). This favorable interaction appears to contribute to the high affinity of 1 for KOR as well as its agonist character.
Figure 2
Figure 2
Modeling of peptide 1 (Tyr-c(S-S)[DCys-Phe-Phe-Cys]NH2) docked in the active and inactive state models of DOR (A and B) and MOR (C and D). Docking of 1 to the active state of DOR shows a steric clash between Phe3 of 1 and Met199 of DOR, highlighted by an arrow in 2A; this steric clash is not seen when 1 is docked in the DOR inactive state binding site or the MOR active or inactive state binding sites.
Figure 3
Figure 3
Modeling of peptide 12 (Tyr-c(S-S)[DCys-1Nal-Nle-Cys]OH) docked in the active state model of MOR (A) and 13 (Tyr-c(S-S)[DCys-1Nal-Nle-DCys]OH) docked in the inactive state model of MOR (B). The C-terminal COO- of 12 forms a favorable ionic interaction with Lys303. However, when 13 is docked in the active site the C-terminal COO- is angled toward Glu229, resulting in an unfavorable repulsion (not shown); in the inactive state, rotation of Glu229 and Lys233 relieves this repulsion and allows a favorable interaction with Lys233.
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