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Development of mixed efficacy opioid ligands
Sean P. Henry , Anthony F. Nastase , Deanna Montgomery
Chronic use of mu-opioid agonists such as morphine has been shown to cause neurochemical adaptations resulting in tolerance and dependence. Tolerance is an adaptation whereby patients (or drug abusers) require increasing doses of drug to achieve the same desired effect. This can be dangerous as not all the effects of opioids develop tolerance. It is known that both the analgesic and rewarding effects of morphine and other abused opioids develop tolerance, other deleterious side effects such as respiratory depression do not. Thus, development of novel ligands that can prevent or lessen the development of tolerance would represent a step forward in the treatment of long-term pain conditions and have a positive impact in treatment of drug abuse.

While the analgesic effects of these drugs are mediated by the mu opioid receptor (MOR), several studies have shown that antagonism or knockdown of the delta opioid receptor (DOR) can lessen or prevent development of tolerance and dependence. Based on computational modeling of putative active and inactive conformations of MOR and DOR, we have focused on the development of mixed-efficacy cyclic pentapeptides that would display MOR agonism and DOR antagonism and prepared a series of naphthylalanine-substituted cyclic pentapeptides (Figure 1). The most promising peptide (Peptide 8; Tyr-c(S-CH2-S)[D-Cys-Phe-2-Nal-Cys]NH2) displayed a MOR agonist and DOR partial agonist/antagonist profile and bound with equipotent affinity (Ki ~ 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity (Figure 2).


Figure 1 : Schematic representation of naphthylalanine-substituted peptides synthesized.


The high binding affinity and efficacy of the naphthylalanine-substituted pentapeptides at the kappa opioid receptor (KOR) was noted as a potential problem as KOR agonists are known to produce dysphoria. Our current focus is the the removal of KOR affinity from peptides using computational modeling to focus new ligand development. Future studies will also be directed at novel scaffolds presenting the desired binding affinity profile with the goal of improving MOR agonism and DOR antagonism.


Figure 2 : Relative efficacies of napthylalanine pentapetide derivatives in MOR (A) and DOR (B) mediated [35S]GTP γS stimulation. Peptides 7 and 8, which demonstrate MOR agonist and DOR antagonist properties, are chosen as lead compounds for further optimization.


In parallel with the development of better MOR agonist/DOR antagonist ligands, we are also working to characterize MOR/DOR interactions using the SH-SY5Y neuroblastoma cell line which endogenously expresses both MOR and DOR. Tolerance to MOR agonists can be demonstrated after chronic mu-opioid exposure in this cell line, as seen in Figure 3.

Figure 3: Development of tolerance in the [35S]GTP γS stimulation assay after pretreatment with MOR agonists DAMGO (left) or morphine (right).


The degree of tolerance exhibited by the cells was greater in those pretreated with 1 μM DAMGO for 24 hours than by 1 μM morphine, due to the fact that DAMGO is a full agonist at MOR while morphine is a partial agonist. The tolerance visualized as a decrease in [35S]GTPγS stimulation is most likely due to MOR internalization or downregulation, and has been confirmed using radioligand binding assays.

Current and planned studies will address the effect of DOR antagonist pretreatment on the development of tolerance to MOR agonist and will also examine whether our mixed MOR agonist/DOR antagonist ligands have a reduced tolerance liability.



Related Publications

Purington LC, Pogozheva ID, Traynor JR, Mosberg HI.
Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties.
J Med Chem, 52(23): 7724-7731 (2009)

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Design and synthesis of biologically active opioid peptides and peptidomimetics
Investigations of MOR and DOR trafficking and crosstalk
Development of mixed efficacy opioid ligands
Peptides and proteins in membranes
Homology modeling of GPCRs, important drug targets
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