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Modulation of Opioid Receptor Ligand Affinity and Efficacy Using Active and Inactive State Receptor Models
Author(s) -
Anand Jessica P.,
Purington Lauren C.,
Pogozheva Irina D.,
Traynor John R.,
Mosberg Henry I.
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12014
Subject(s) - chemistry , agonist , receptor , intrinsic activity , opioid receptor , ligand (biochemistry) , δ opioid receptor , opioid , pharmacology , stereochemistry , antagonist , partial agonist , functional selectivity , biochemistry , biology
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.