Transformation of μ-opioid receptor agonists into biologically potent μ-opioid receptor antagonists

[N-Allyl-Dmt1]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

“…1 ]-endomorphin-1 and -2 are MOP antagonists as measured by functional bioassays using guinea pig ileum and mouse vas deferens (Li et al, 2007). The results reported herein demonstrated that they behave as neutral antagonists (Fig.…”

“…In the present study, we have applied SK-N-SH cells, which constitutively express MOP, for the characterization of [N-allyl-Dmt 1 ]-endomorphin-1 and -2, high-affinity -opioid antagonists (Li et al, 2007). It is noteworthy that the K i values obtained from SK-N-SH cell membranes were essentially identical to those obtained from rat brain synaptosomes (Li et al, 2007).…”

“…[N-Allyl-Dmt 1 ]-endomorphin-1 (N-allyl-Dmt-Pro-Trp-Phe-NH 2 ) and [N-allyl-Dmt 1 ]-endomorphin-2 (N-allyl-Dmt-ProPhe-Phe-NH 2 ) are new MOP antagonists obtained by N-alkylation with a single allyl group (CH 2 ϭCH-CH 2 -) on the amino terminus of Dmt 1 (2Ј,6Ј-dimethyl-L-tyrosine), a residue that enhances peptide stability, alters ligand interaction with opioid receptors, and affects bioactivity to exhibit high MOP affinity (K i ϭ 0.26 -0.45 nM) and MOP antagonism (pA 2 ϭ 8.18 -8.59) (Li et al, 2007). Intracerebroventricular and subcutaneous injection of [N-allyl-Dmt 1 ]-EM-1 or -2 inhibited morphine-induced analgesia in mice, whereas [N-allyl-Dmt 1 ]-EM-2 also inhibited ethanol-induced frequency of spontaneous inhibitory postsynaptic currents (a component of GABA A receptor-mediated neuronal function) in hippocampal slices from rat brain, suggesting its potential application in treatment of alcohol dependence (Li et al, 2007).…”

“…Intracerebroventricular and subcutaneous injection of [N-allyl-Dmt 1 ]-EM-1 or -2 inhibited morphine-induced analgesia in mice, whereas [N-allyl-Dmt 1 ]-EM-2 also inhibited ethanol-induced frequency of spontaneous inhibitory postsynaptic currents (a component of GABA A receptor-mediated neuronal function) in hippocampal slices from rat brain, suggesting its potential application in treatment of alcohol dependence (Li et al, 2007). To further characterize the properties of [N-allyl-Dmt 1 ]-EM-1 and -2, their intrinsic activities were assessed by functional [ 35 S]GTP␥S binding and forskolin-stimulated cyclic AMP accumulation assays in cell membranes isolated from vehicle, morphine, and ethanol-treated SK-N-SH cells (as model systems of naive and opiate or ethanol-dependent conditions), and in brain membranes isolated from opioid-naive and morphine-dependent mice and compared with the effects produced by naloxone and naltrexone.…”

Design, Synthesis and Pharmacological Evaluation of Novel Endomorphin Analogues with Multiple Structural Modifications

“…Furthermore, incorporation of N-allylDmt 1 in EM-1 and -2 resulted in neutral µ-opioid antagonists, these analogues inhibited the naloxone/naltrexone-elicited withdrawal syndromes without adverse effects observed with inverse agonist alkaloid-derived compounds [56,57]. But, the substitution of N, Nallyl-Dmt 1 yielded a decreased µ-opioid receptor affinity which suggests that the presence and the conformation of Tyr 1 is crucial for interaction with opioid receptors.…”