Design, Synthesis, and Biological Evaluation of 6α- and 6β-N-Heterocyclic Substituted Naltrexamine Derivatives as μ Opioid Receptor Selective Antagonists

Abstract

Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible μ opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K i = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the δ receptor (DOR) and more than 150-fold selectivity over the κ receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.

Characterization of 6α- and 6β-N-Heterocyclic Substituted Naltrexamine Derivatives as Novel Leads to Development of Mu Opioid Receptor Selective Antagonists

“…Accordingly, when incubated alone (in the absence of DAMGO), both lead compounds produced low levels of stimulation (∼15% of DAMGO), indicating that they are partial agonists of low relative efficacy in thalamus. These results are consistent with the ones previously observed in an MORtransfected CHO cell line, 20 and confirm that these lead compounds are low efficacy partial agonists of the MOR.…”

“…As antagonists, their potency (NAP AD 50 was 4.98 mg/kg and NAQ was 0.46 mg/kg) was lower than that of naloxone (at 0.05 mg/kg). 20 Apparently, this is not consistent with their in vitro high potency.…”

“…20 Among them, NAP and NAQ ( Figure 1) seemed to be promising leads as MOR selective antagonists. NAP displayed high binding affinity for the MOR at K i = 0.37 nM with over 700-fold selectivity for the MOR over the DOR and more than 150-fold selectivity over the KOR.…”

Preclinical Disposition (In Vitro) of Novel μ-Opioid Receptor Selective Antagonists

“…1), exhibited high selectivity for the MOR relative to naltrexone. Both compounds also exhibited comparable antagonistic activity at the MOR and insignificant agonistic activity (Li et al, 2009). These results piqued interest in the potential clinical use of NAP and NAQ.…”

“…NAP and NAQ were synthesized as described previously (Li et al, 2009). The Caco-2 cells were obtained from American Type Culture Collection (Manassas, VA).…”