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1.  DOR activation inhibits anoxic/ischemic Na+ influx through Na+ channels via PKC mechanisms in the cortex 
Experimental neurology  2012;236(2):228-239.
Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na+ influx through TTX-sensitive voltage-gated Na+ channels may be a main mechanism for hypoxia-induced disruption of K+ homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na+ channels. In the present study we examined the role of DOR in the regulation of Na+ influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na+ influx induced by a Na+ channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na+ activity in mouse cortical slices with Na+ selective electrodes and found that (1) anoxia-induced Na+ influx occurred mainly through TTX-sensitive Na+ channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na+ influx; (3) veratridine, a Na+ channel opener, enhanced the anoxia-induced Na+ influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na+ influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKCβII peptide inhibitor, and PKCθ pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na+ influx through Na+ channels via PKC (especially PKCβII and PKCθ isoforms) dependent mechanisms in the cortex.
PMCID: PMC3465681  PMID: 22609332
Delta-opioid receptor; Ionic homeostasis; Na+ influx; Na+ channel; Neuroprotection; Hypoxia/ischemia
2.  Current Research on Opioid Receptor Function 
Current Drug Targets  2012;13(2):230-246.
The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor.
In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction.
The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.
PMCID: PMC3371376  PMID: 22204322
Opioids; opioid receptors; neurotransmitters; function; brain; heart; lung; ionic homeostasis; neuroprotection; hibernation; pain; hypoxia; ischemia
3.  Engineering endomorphin drugs: state of the art 
Importance of the field
Although EM-1 (H-Tyr-Pro-Phe-Trp-NH2) and EM-2 (H-Tyr-Pro-Phe-Phe-NH2) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties suitable for application to health related topics.
Areas covered in this review
This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand.
What the reader will gain
While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimental delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability, formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential.
Take home message
Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction.
PMCID: PMC3253703  PMID: 22214283
endomorphins; opioid receptors; rational drug design; agonists; antagonists; peptide synthesis
4.  Developmental Potential for Endomorphin Opioidmimetic Drugs 
Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM)-1 and endomorphin(EM)-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr1 with 2′,6′-dimethyl-l-tyrosine (Dmt) to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt1]EM-1 and [Dmt1]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt1]EM-1 (47) and [N-allyl-Dmt1]EM-2 (48) exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier.
PMCID: PMC4411882  PMID: 25954530
5.  Opioid Bifunctional Ligands from Morphine and the Opioid Pharmacophore Dmt-Tic 
Bifunctional ligands containing an ester linkage between morphine and the δ-selective pharmacophore Dmt-Tic were synthesized, and their binding affinity and functional bioactivity at the μ, δ and κ opioid receptors determined. Bifunctional ligands containing or not a spacer of β-alanine between the two pharmacophores lose the μ agonism deriving from morphine becoming partial μ agonists 4 or μ antagonists 5. Partial κ agonism is evidenced only for compound 4. Finally, both compounds showed potent δ antagonism.
PMCID: PMC3035428  PMID: 21216504
6.  Role of 2′,6′-Dimethyl-L-Tyrosine (Dmt) in Some Opioid Lead Compounds 
Bioorganic & medicinal chemistry  2010;18(16):6024-6030.
Here we evaluated how the interchange of the amino acids 2′,6′-dimethyl-L-tyrosine (Dmt), 2′,6′-difluoro-L-tyrosine (Dft), and tyrosine in position 1 can affect the pharmacological characterization of some reference opioid peptides and pseudopeptides. Generally, Dft and Tyr provide analogues with a similar pharmacological profile, despite different pKa values. Dmt/Tyr(Dft) replacement gives activity changes depending on the reference opioid in which the modification was made. Whereas, H-Dmt-Tic-Asp*-Bid is a potent and selective δ agonist (MVD, IC50 = 0.12 nM); H-Dft-Tic-Asp*-Bid and H-Tyr-Tic-Asp*-Bid are potent and selective δ antagonists (pA2 = 8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt1 and Dft1 analogues, the three compounds maintain a very similar δ agonism (MVD, IC50 0.32–0.53 nM) with a decrease in selectivity relative to the Dmt1 analogue. In the less selective H-Dmt-Tic-Gly*-Bid the replacement of Dmt with Dft and Tyr retains the δ agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr.
PMCID: PMC2918654  PMID: 20637637
Dmt-Tic pharmacophore; opioid peptides; opioid receptors; δ opioid agonists; UFP-512; δ opioid antagonists
7.  δ-opioid receptors protect from anoxic disruption of Na+ and K+ homeostasis via Na+ channel regulation 
Hypoxic/ischemic disruption of ionic homeostasis, especially Na+ influx and K+ leakage, is a critical trigger of neuronal injury/death in the brain. There is, however, no promising strategy against such pathophysiological changes to protect the brain from hypoxic/ischemic injury. Here we present an exciting finding that activation of delta-opioid receptor (DOR), which is highly expressed in the cortex, reduced anoxic Na+ influx and K+ leakage in the cortex by restricting Na+ influx through voltage-gated Na+ channels. Furthermore, we show for the first time with direct evidence that DOR expression/activation indeed plays an inhibitory role in Na+ channel regulation by decreasing the amplitude of sodium currents and increasing activation threshold of Na+ channels. These first data have far-reaching impacts on understanding the intrinsic mechanism of neuronal responses to stress and provide novel insights into better solutions of hypoxic/ischemic encephalopathy and other neurological disorders such as epilepsy and pain.
PMCID: PMC3061309  PMID: 19756387
δ-opioid receptors; Na+ channels; anoxia; Na+ influx; K+ efflux; neuroprotection
8.  Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds 
The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity. Whereas the Tic- and Aba multimers proved to be dual and balanced δ/μ antagonists, as determined by the functional [S35]GTPγS binding assay, the dimerization of potent Aia-based ‘parent’ ligands unexpectedly resulted in substantial less efficient receptor binding and non-active dimeric compounds.
PMCID: PMC2840614  PMID: 20137938
9.  Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore 
ACS chemical neuroscience  2010;1(2):155-164.
Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH3, partially −NO2, inactive -NH2) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA2 = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.
PMCID: PMC2843921  PMID: 20352071
10.  Evolution of the Bifunctional Lead μ Agonist/δ Antagonist Containing the 2′,6′-Dimethyl-l-tyrosine−1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Dmt−Tic) Opioid Pharmacophore 
ACS Chemical Neuroscience  2009;1(2):155-164.
Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist/δ antagonist, H-Dmt-Tic-Gly-NH-Bzl (Dmt = 2′,6′-dimethyl-l-tyrosine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Bzl = benzyl). Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (−Cl, −CH3, partially −NO2, inactive −NH2) was found to give a more potent μ agonist/antagonist effect associated with a relatively unmodified δ antagonist activity (pA2 = 8.28−9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly d-Tic2, considered as a wrong opioid message now, inserted into the reference compound in lieu of l-Tic provided a μ agonist/δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph; Ph = phenyl) and was endowed with the same pharmacological profile.
PMCID: PMC2843921  PMID: 20352071
Bifunctional opioids; Dmt−Tic pharmacophore; opioid peptides; opioid receptors, angiogenesis, tolerance
11.  A novel insight into neuroprotection against hypoxic/ischemic stress 
The use of opioid analgesics has a long history in clinical settings, although the functions of opioid receptors, especially their role in the brain, are not well understood yet. Recent studies have generated abundant new data on opioid receptor-mediated functions and the underlying mechanisms. The most exciting finding in the past decade is probably the neuroprotection against hypoxic/ischemic stress mediated by δ-opioid receptors (DOR). An up-regulation of DOR expression and the release of endogenous opioids may increase neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers, depending on stress duration and severity, different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of ionic homeostasis, an increase in pro-survival signaling (e.g., PKC-ERK-Bcl 2) and the enhanced anti-oxidative capacity. Recent data on DOR-mediated neuroprotection provide us a new concept of neuroprotection against neurological disorders and have a potentially significant impact on the prevention and treatment of some serious neurological conditions, such as stroke.
PMCID: PMC3034294  PMID: 20029693
opioids; δ-opioid receptors; neurotransmitters; brain; ionic homeostasis; neuroprotection; hypoxia; ischemia
12.  Prototypic Opioid Peptidomimetics Based on the Dmt-Aba-Gly Scaffold 
Journal of medicinal chemistry  2006;49(13):3990-3993.
Peptidomometic analogues, H-Dmt-Tic-NH2-CH2-Ph or -Bid exhibit δ-opioid receptor activities. Substitution of Tic by the Aba-Gly scaffold coupled to the C-termini -CH2-Ph (1), -NH-Ph (2) and Gly*-Bid (3) shifted receptor affinity and selectivity to μ-opioid receptors (Kiμ = 0.46, 1.48 and 19.9 nM, respectively) with μ agonism. These represent templates for a new class of μ-opioid agonists. Further modification with negative or positive charges could yield altered properties suitable for therapeutic application for pain relief.
PMCID: PMC2983084  PMID: 16789756
13.  Orally administered H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2), a potent μ-/δ-opioid receptor antagonist, regulates obese-related factors in mice 
European journal of pharmacology  2009;616(1-3):115-121.
Orally active dual μ-/δ-opioid receptor antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2) was applied to study body weight gain, fat content, bone mineral density, serum insulin, cholesterol and glucose levels in female ob/ob (B6.V-Lep/J homozygous) and lean wild mice with or without voluntary exercise on wheels for three weeks, and during a two week post-treatment period under the same conditions. MZ-2 (10 mg/kg/day, p.o.) exhibited the following actions: (1) reduced body weight gain in sedentary obese mice that persisted beyond the treatment period without effect on lean mice; (2) stimulated voluntary running on exercise wheels of both groups of mice; (3) decreased fat content, enhanced bone mineral density (BMD), and decreased serum insulin and glucose levels in obese mice; and (4) MZ-2 (30 μM) increased BMD in human osteoblast cells (MG-63) comparable to naltrexone, while morphine inhibited mineral nodule formation. Thus, MZ-2 has potential application in the clinical management of obesity, insulin and glucose levels, and the amelioration of osteoporosis.
PMCID: PMC2750889  PMID: 19576206
obesity; ob/ob mice; bone mineral density; insulin; glucose; Dmt-Tic pharmacophore; dual μ-/δ-opioid receptor antagonist
14.  Na+ mechanism of δ-opioid receptor induced protection from anoxic K+ leakage in the cortex 
Activation of δ-opioid receptors (DOR) attenuates anoxic K+ leakage and protects cortical neurons from anoxic insults by inhibiting Na+ influx. It is unknown, however, which pathway(s) that mediates the Na+ influx is the target of DOR signal. In the present work, we found that in the cortex, 1) DOR protection was largely dependent on the inhibition of anoxic Na+ influxes mediated by voltage-gated Na+ channels; 2) DOR activation inhibited Na+ influx mediated by ionotropic glutamate NMDA receptors, but not that by non-NMDA receptors though both played a role in anoxic K+ derangement; and 3) DOR activation had little effect on Na+/Ca2+ exchanger-based response to anoxia. We conclude that, 1) DOR activation attenuates anoxic K+ derangement by restricting Na+ influx mediated by Na+ channels and NMDA receptors, and 2) non-NMDA receptors and Na+/Ca2+ exchangers, though involved in anoxic K+ derangement in certain degrees, are less likely the targets of DOR signal.
PMCID: PMC2704459  PMID: 19189047
anoxia; cortex; δ-opioid receptor; K+ homeostasis; Na+ channels; ionotropic glutamate receptor channels
15.  Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic 
Journal of medicinal chemistry  2008;51(16):5109-5117.
Opioids containing the Dmt-Tic pharmacophore, especially the δ agonists H-Dmt-Tic-Gly-NH-Ph 1 and H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid 4 (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the – NH-Ph and N1H-Bid hydrogens relative to δ agonism. The results provide the following conclusions: (i) Asp increases δ selectivity by lowering μ affinity; (ii) -NH-Ph and N1H-Bid nitrogen methylation transforms δ agonists into δ antagonists; (iii) substitution of Gly with L-Asp/D-Asp in the δ agonist H-Dmt-Tic-Gly-NH-Ph resulted in δ antagonists, while the same substitution in the δ agonist H-Dmt-Tic-NH-CH2-Bid yielded more selective δ agonists, H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid and H-Dmt-Tic-NH-(R)CH(CH2-COOH)-Bid; (iv) L-Asp seems important only for functional bioactivity, not receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid(N1-Me) (10) revealed analgesia similar to 4, which was reversed by naltrindole only in the tail-flick test. Compounds 4 and 10 had opposite behaviours in mice: 4 caused agitation, while 10 gave sedation and convulsions.
PMCID: PMC2812024  PMID: 18680274
16.  Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia vs. Dmt-Tic scaffold 
Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent μ-selective agonists (Structures 5 and 12) as well as potent and selective δ-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small peptidomimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure-activity data.
PMCID: PMC2742322  PMID: 19062273
17.  The Novel μ-Opioid Receptor Antagonist, [N-Allyl-Dmt1]Endomorphin-2, Attenuates the Enhancement of GABAergic Neurotransmission by Ethanol 
Aims: We investigated the effects of [N-allyl-Dmt1]endomorphin-2 (TL-319), a novel and highly potent μ-opioid receptor antagonist, on ethanol (EtOH)-induced enhancement of GABAA receptor-mediated synaptic activity in the hippocampus. Methods: Evoked and spontaneous inhibitory postsynaptic currents (eIPSCs and sIPSCs) were isolated from CA1 pyramidal cells from brain slices of male rats using whole-cell patch-clamp techniques. Results: TL-319 had no effect on the baseline amplitude of eIPSCs or the frequency of sIPSCs. However, it induced a dose-dependent suppression of an ethanol-induced increase of sIPSC frequency with full reversal at concentrations of 500 nM and higher. The non-specific competitive opioid receptor antagonist naltrexone also suppressed EtOH-induced increases in sIPSC frequency but only at a concentration of 60 μM. Conclusion: These data indicate that blockade of μ-opioid receptors by low concentrations of [N-allyl-Dmt1]endomorphin-2 can reverse ethanol-induced increases in GABAergic neurotransmission and possibly alter its anxiolytic or sedative effects. This suggests the possibility that high potency opioid antagonists may emerge as possible candidate compounds for the treatment of ethanol addiction.
PMCID: PMC2724860  PMID: 18971291
18.  Inhibition of the Development of Morphine Tolerance by a Potent Dual μ-/δ-Opioid Antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph 
Three analogues of the dual μ-/δ-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (δ-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a μ antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.
PMCID: PMC2597683  PMID: 18571706
H-Dmt-Tic-Lys-NH-CH2-Ph; Antinociception; Tolerance; Spinal; Dual μ-/δ-opioid antagonist
19.  Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides 
Bioorganic & medicinal chemistry  2008;16(11):6286-6296.
Endomorphin 1 (Endo-1 = Tyr-Pro-Trp-Phe-NH2), an endogenous opioid with high affinity and selectivity for μ-opioid receptors, mediates acute and neuropathic pain in rodents. To overcome metabolic instability and poor membrane permeability, the N- and C-termini of Endo-1 were modified by lipoamino acids (Laa) and/or sugars, and 2′,6′-dimethyltyrosine (Dmt) replacement of Tyr. Analogues were assessed for μ-opioid receptor affinity, inhibition of cAMP accumulation, enzymatic stability, and permeability across Caco-2 cell monolayers. C-terminus modification decreased receptor affinity, while N-terminus C8-Laa improved stability and permeability with slight change in receptor affinity. Dmt provided a promising lead compound: [C8Laa-Dmt1]-Endo-1 is 9 times more stable (t½ = 43.5 min), > 8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater μ-opioid receptor affinity (Kiμ = 0.08 nM).
PMCID: PMC2643467  PMID: 18468445
Endomorphin 1; opioid peptides; lipoamino acids; liposaccharides; peptide delivery
20.  Bifunctional [2’,6’-Dimethyl-l-tyrosine1]Endomorphin-2 Analogues Substituted at Position 3 with Alkylated Phenylalanine Derivatives Yield Potent Mixed μ-Agonist/δ-Antagonist and Dual μ-/δ-Agonist Opioid Ligands 
Journal of medicinal chemistry  2007;50(12):2753-2766.
Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and [Dmt1]EM-2 (Dmt = 2’,6’-dimethyl-l-tyrosine) analogues were synthesized containing alkylated Phe3 derivatives, 2’-monomethyl (2, 2’), 3’,5’- and 2’,6’-dimethyl (3, 3’, and 4’, respectively), 2’,4’,6’-trimethyl (6, 6’), 2’-ethyl-6’-methyl (7, 7’) and 2’-isopropyl-6’-methyl (8, 8’) groups or Dmt (5, 5’). They had the following characteristics: (i) [Xaa3]EM-2 analogues improved μ- and δ-opioid receptor affinities, the latter were inconsequential (Kiδ= 491–3,451 nM); (ii) [Dmt1,Xaa3]EM-2 analogues enhanced μ- and δ-opioid receptor affinities (Kiμ = 0.069–0.32 nM; Kiδ = 1.83–99.8 nM) and lacked interaction with κ-opioid receptors, and (iii) elevated μ-bioactivity (IC50 = 0.12–14.4 nM) and abolished δ-agonism (IC50 > 10 µM; 2’, 3’, 4’, 5’, 6’); however, 4’ and 6’ exhibited mixed μ-agonism/δ-antagonism (4’: IC50μ = 0.12, pA2 = 8.15; 6’: IC50μ = 0.21 nM, pA2 = 9.05), and 7’ was a dual μ-/δ -agonist (IC50μ = 0.17 nM; IC50δ = 0.51 nM). Alteration of EM-2 activity by Dmt1 and alkylated Phe3 residues retained μ-receptor bioactivity and formed dual μ-/δ -agonists and mixed μ-agonists/δ-antagonists.
PMCID: PMC2669435  PMID: 17497839
21.  Synthesis of a potent and selective 18F-labeled δ-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for PET imaging 
Journal of medicinal chemistry  2008;51(6):1817-1823.
H-Dmt-Tic-ε-Lys(Z)-OH (1) was used in the synthesis of 18F-labeled opioids for positron emission tomography (PET) imaging by coupling N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) with Boc-Dmt-Tic-ε-Lys(Z)-OH under slightly basic conditions at 37 °C for 15 min, deprotected with TFA and HPLC purification in 120 min with a decay-corrected radiochemical 25–30% yield of [18F]-1 (n = 5) and specific activity ca. 46 GBq/µmol. Autoradiography uptake of [18F]-1 in striatum and cortex was blocked by 1 and UFP-501 demonstrating specific binding to δ-opioid receptors. MicroPET imaging revealed the absence of [18F]-1 in rat brain, suggesting its suitability for imaging peripheral δ-opioid receptors.
PMCID: PMC2667121  PMID: 18311909
22.  Role of Benzimidazole (Bid) in the δ Opioid Agonist Pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502) 
Bioorganic & medicinal chemistry  2007;16(6):3032-3038.
H-Dmt-Tic-NH-CH2-Bid (UFP-502) was the first δ opioid agonist prepared from the Dmt-Tic pharmacophore. It showed interesting pharmacological properties, such as stimulation of mRNA BDNF expression, and antidepression. To evaluate the importance of 1H-benzimidazol-2-yl (Bid) in the induction of δ agonism, it was substituted by similar heterocycles: The substitution of NH(1) by O or S, transforms the reference δ agonist into δ antagonists. Phenyl ring of benzimidazole is not important for δ agonism; in fact 1H-imidazole-2-yl retains δ agonist activity.
PMCID: PMC2390930  PMID: 18178091
23.  Synthesis of 3,6-bis[H-Tyr/H-Dmt-NH(CH2)m,n]-2(1H)pyrazinone derivatives: function of alkyl chain length on opioid activity 
Dimeric opioid analogues linked to a pyrazinone platform, 3-[Tyr-NH(CH2)m]-6-[Tyr-NH(CH2)n]-2(1H)-pyrazinone (n, m = 3 or 4) and their corresponding Dmt derivatives were synthesized. Whereas the Try-containing compounds were essentially inactive, the Dmt derivatives exhibited high affinity for the µ-opioid receptor (Kiµ; 0.021–0.051 nM) with corresponding agonism (IC50 = 1.79–4.93 nM). Interestingly, while one compound (m = 4, n = 3) revealed modest δ-agonism, the converse analogue (m = 3, n = 4) was inactive. The data suggest that the spatial conformation, linker length and covalent bonding position on the pyrazinone ring are important for opioid activity.
PMCID: PMC2636969  PMID: 16949282
24.  Conversion of the Potent δ-Opioid Agonist H-Dmt-Tic-NH-CH2-Bid into δ-Opioid Antagonists by N1-Benzimidazole Alkylation1 
Journal of medicinal chemistry  2005;48(26):8112-8114.
N1-Alkylation of 1H-benzimidizole of the δ agonist H-Dmt-Tic-NH-CH2-Bid with hydrophobic, aromatic, olefinic, acid, ethyl ester or amide (1–6) became δ antagonists (pA2 = 8.52–10.14). δ- and μ-Opioid receptor affinities were high (Kiδ = 0.12–0.36 nM and Kiμ = 0.44–1.42 nM). Only δ antagonism (pA2 = 8.52–10.14) was observed; μ agonism (IC50 = 30–450 nM) was not correlated with changes in alkylating agent or δ antagonism and some compounds yielded mixed δ antagonism/μ agonism.
PMCID: PMC2597450  PMID: 16366592
25.  A new opioid designed multiple ligand derived from the μ opioid agonist endomorphin-2 and the δ opioid antagonist pharmacophore Dmt-Tic 
Bioorganic & medicinal chemistry  2007;15(22):6876-6881.
Opioid compounds with mixed μ agonist / δ antagonist properties could be used as analgesics with low propensity to induce tolerance and dependence. Here we report the synthesis of a new designed multiple ligand deriving from the μ selective agonist endomorphin-2 and the δ selective antagonist pharmacophore Dmt-Tic. As predicted, the resulting bivalent ligand showed a μ agonist / δ antagonist profile deriving from the corresponding activities of each pharmacophore.
PMCID: PMC2084217  PMID: 17851080
Designed multiple ligand; Endomorphin-2; Dmt-Tic pharmacophore; Analgesia; Physical dependence

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