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1.  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
2.  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
3.  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
4.  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
5.  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
6.  Effect of Lysine at C-Terminus of the Dmt-Tic Opioid Pharmacophore 
Journal of medicinal chemistry  2006;49(18):5610-5617.
Substitution of Gly with side-chain protected or unprotected Lys in lead compounds containing the opioid pharmacophore Dmt-Tic [H-Dmt-Tic-Gly-NH-CH2-Ph, μ agonist / δ antagonist; H-Dmt-Tic-Gly-NH-Ph, μ agonist / δ agonist and H-Dmt-Tic-NH-CH2-Bid, δ agonist (Bid = 1H-benzimidazole-2-yl)] yielded a new series of compounds endowed with distinct pharmacological activities. Compounds (1-10) included high δ- (Kiδ = 0.068-0.64 nM) and μ-opioid affinities (Kiδ = 0.13-5.50 nM) with a bioactivity that ranged from μ-opioid agonism {10, H-Dmt-Tic-NH-CH[(CH2)4-NH2]-Bid (IC50 GPI = 39.7 nM)} to a selective μ-opioid antagonist [3, H-Dmt-Tic-Lys-NH-CH2-Ph (pA2μ = 7.96)] and a selective δ-opioid antagonist [5, H-Dmt-Tic-Lys(Ac)-NH-Ph (pA2δ = 12.0)]. The presence of a Lys linker provides new lead compounds in the formation of opioid peptidomimetics containing the Dmt-Tic pharmacophore with distinct agonist and / or antagonist properties.
PMCID: PMC2533050  PMID: 16942034
7.  New Opioid Designed Multiple Ligand from Dmt-Tic and Morphinan Pharmacophores 
Journal of medicinal chemistry  2006;49(18):5640-5643.
Here we report the facile synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu / kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as the two reference compounds. MCL 450 represents a useful starting point for the synthesis of other multiple opioid ligands endowed with analgesic properties with low tolerance and dependence.
PMCID: PMC2435260  PMID: 16942040
8.  6-N,N-Dimethylamino-2,3-Naphthalimide a New Environment-Sensitive Fluorescent Probe in δ-Selective and μ-Selective Opioid Peptides 
Journal of medicinal chemistry  2006;49(12):3653-3658.
A new environment-sensitive fluorophore, 6-N,N-dimethylamino-2,3-naphthalimide (6DMN) was introduced in the δ-selective opioid agonist H-Dmt-Tic-Glu-NH2 and in the μ-selective opioid agonist endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2). Environment sensitive fluorophores are a special class of chromophores that generally exhibit a low quantum yield in aqueous solution, but become highly fluorescent in nonpolar solvents or when bound to hydrophobic sites in proteins or membranes. New fluorescent δ-selective irreversible antagonists [H-Dmt-Tic-Glu-NH-(CH2)5-CO-Dap(6DMN)-NH2(1) and H-Dmt-Tic-Glu-Dap(6DMN)-NH2)] (2) were identified as potential fluorescent probes showing properties suitable for studies of distribution and internalization of δ-opioid receptors by confocal laser scanning microscopy.
PMCID: PMC1994907  PMID: 16759107

Results 1-8 (8)