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1.  Truncation of the peptide sequence in bifunctional ligands with mu and delta opioid receptor agonist and neurokinin 1 receptor antagonist activities 
Bioorganic & medicinal chemistry letters  2013;23(17):10.1016/j.bmcl.2013.06.065.
The optimization and truncation of our lead peptide-derived ligand TY005 possessing eight amino-acid residues was performed. Among the synthesized derivatives, NP30 (Tyr1-DAla2-Gly3-Phe4-Gly5-Trp6-O-[3′,5′-Bzl(CF3)2]) showed balanced and potent opioid agonist as well as substance P antagonist activities in isolated tissue-based assays, together with significant antinociceptive and antiallodynic activities in vivo.
PMCID: PMC3810412  PMID: 23899615
bifunctional compounds; opioid receptor agonists; neutokinin-1 receptor antagonists; Truncation of peptide sequence; NMR structure
2.  Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands 
Bioorganic & medicinal chemistry  2011;19(20):6135-6142.
Newly designed bivalent ligands—opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials—carboxy-derivatives of Fentanyl (1a–1c) was developed. These products have been transformed to ‘isoimidium perchlorates’ (2a–c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds—amides (3a–c). Perchlorates (2a–c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.
PMCID: PMC4137774  PMID: 21925887
Analgesic; Bivalent ligands; μ-Opioids; NK1 antagonist; Fentanyl
3.  Chiral Effect of a Phe Residue in Position 3 of the Dmt1-l(or d)-Tic2 Analogues on Opioid Functional Activities 
ACS Medicinal Chemistry Letters  2013;4(7):656-659.
In this letter, we describe a structure–activity relationships study, specifically related to the chirality of third amino acid residue in our H-Dmt-l(or d)-Tic analogues, of which C-terminus is attached to a piperidinyl moiety. Observed selectivities and functional activities of these analogues demonstrated that the chiralities of the second and third position residues are crucial for determining whether these ligands act as antagonists or agonists at the δ opioid receptor, but not at the μ opioid receptor.
PMCID: PMC3956057  PMID: 24648867
Dmt-Tic; opioid functional activities; structure−activity relationship; δ opioid receptor; chirality
4.  Chiral Effect of a Phe Residue in Position 3 of the Dmt1-L(or D)-Tic2 Analogues on Opioid Functional Activities 
ACS medicinal chemistry letters  2013;4(7):656-659.
In this letter, we describe a structure–activity relationships study, specifically related to the chirality of third amino acid residue in our H-Dmt-L(or D)-Tic analogues, of which C-terminus is attached to a piperidinyl moiety. Observed selectivities and functional activities of these analogues demonstrated that the chiralities of the second and third position residues are crucial for determining whether these ligands act as antagonists or agonists at the δ opioid receptor, but not at the μ opioid receptor.
PMCID: PMC3956057  PMID: 24648867
Dmt-Tic; opioid functional activities; structure–activity relationship; δ opioid receptor; chirality
5.  Effect of anchoring 4-anilidopiperidines to opioid peptides 
We report here the design, synthesis, and in vitro characterization of new opioid peptides featuring a 4-anilidopiperidine moiety. Despite the fact that the chemical structures of fentanyl surrogates have been found suboptimal per se for the opioid activity, the corresponding conjugates with opioid peptides displayed potent opioid activity. These studies shed an instructive light on the strategies and potential therapeutic values of anchoring the 4-anilidopiperidine scaffold to different classes of opioid peptides.
PMCID: PMC3942532  PMID: 23623418
Opioid peptide; Dynorphine analog; Bivalent ligand; Fentanyl; Analgesic
6.  Biological Active Analogues of the Opioid Peptide Biphalin: Mixed α/β3-Peptides 
Journal of medicinal chemistry  2013;56(8):3419-3423.
Natural residues of the dimeric opioid peptide Biphalin were replaced by the corresponding homo-β3 amino acids. The derivative 1 containing hβ3 Phe in place of Phe showed good μ- and δ-receptor affinities ( Kiδ=0.72nM;Kiμ=1.1nM) and antinociceptive activity in vivo together with an increased enzymatic stability in human plasma.
PMCID: PMC3942533  PMID: 23547584
7.  Afferent Drive Elicits Ongoing Pain in a Model of Advanced Osteoarthritis 
Pain  2012;153(4):924-933.
Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (i.e., ongoing pain)that is generally resistant to non-steroidal anti-inflammatory drugs (NSAIDs). Injection of monosodium iodoacetate (MIA) into the intra-articular space of the rodent knee is a well-established model of OA that elicits weight-bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intra-articular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA-induced weight asymmetry but failed to block MIA-induced ongoing pain. Systemic AMG9810, a TRPV1 antagonist, effectively blocked thermal hypersensitivity, but failed to block high dose MIA-induced weight asymmetry or ongoing pain. Additionally, systemic or intra-articular HC030031, a TRPA1 antagonist, failed to block high dose MIA-induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intra-articular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery.
PMCID: PMC3313555  PMID: 22387095
8.  Improving Metabolic Stability By Glycosylation: Bifunctional Peptide Derivatives That Are Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists 
Journal of medicinal chemistry  2009;52(16):5164-5175.
In order to obtain a metabolically more stable analgesic peptide derivative, O-β-glycosylated serine (Ser(Glc)) was introduced into TY027 (Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3’,5’-Bzl(CF3)2) which was a previously reported bifunctional compound with delta/mu opioid agonist and neurokinin-1 receptor antagonist activities, and with a half life of 4.8 h in rat plasma. Incorporation of Ser(Glc) into various positions of TY027 gave analogues with variable bioactivities. Analogue 6 (Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3’,5’-Bzl(CF3)2) was found to have effective bifunctional activities with a well-defined conformation with two β-turns based on the NMR conformational analysis in the presence of DPC micelles. In addition, 6 showed significant improvement in its metabolic stability (70 ± 9 % of 6 was intact after 24 h incubation in rat plasma). This improved metabolic stability, along with its effective and delta selective bifunctional activities, suggests that 6 could be an interesting research tool and possibly a promising candidate as a novel analgesic drug.
PMCID: PMC3521585  PMID: 20560643
bifunctional peptide derivatives; glycopeptides; analgesics; opioid induced tolerance; opioid receptor agonist; neurokinin-1 receptor antagonist; conformation-activity relationships; NMR structure; DPC micelles
9.  Discovery of a Potent and Efficacious Peptide Derivative for δ/μ Opioid Agonist/Neurokinin 1 Antagonist Activity with a 2′, 6′-Dimethyl-L-Tyrosine: In Vitro, In Vivo and NMR-Based Structural Studies 
Journal of medicinal chemistry  2011;54(7):2029-2038.
Multivalent ligands with delta/mu opioid agonist and NK1 antagonist activities have shown promising analgesic potency without detectable sign of toxicities, including motor skill impairment and opioid-induced tolerance. To improve their biological activities and metabolic stability, structural optimization was performed on our peptide-derived lead compounds by introducing 2′, 6′-Dimethyl-L-Tyrosine (Dmt) instead of Tyr at the first position. The compound 7 (Dmt-D-Ala-Gly-Phe-MetPro-Leu-Trp-NH-[3′,5′-(CF3)2-Bzl]) showed improved multivalent bioactivities compared to those of the lead compounds, had more than 6 h half-life in rat plasma, and significant antinociceptive efficacy in vivo. The NMR structural analysis suggested that Dmt1 incorporation in compound 7 induces the structured conformation in the opioid pharmacophore (N-terminus), and simultaneously shifts the orientation of the NK1 pharmacophore (C-terminus), consistent with its affinities and activities at both opioid and NK1 receptors. These results indicate that compound 7 is a valuable research tool to seek a novel analgesic drug.
PMCID: PMC3090346  PMID: 21366266
analgesics; bifunctional peptide derivatives; 2′, 6′-Dimethyl-L-Tyrosine; DPC micelle; opioid induced tolerance; opioid receptor agonist; neurokinin-1 receptor antagonist; NMR structure
10.  Development of potent μ and δ opioid agonists with high lipophilicity 
Journal of medicinal chemistry  2010;54(1):382-386.
An SAR study on the Dmt-substituted enkephalin-like tetrapeptide with a N-phenyl-N-piperidin-4-yl propionamide moiety at C-terminal was performed, and has resulted in highly potent ligands at μ and δ opioid receptors. In general, ligands with the substitution of D-Nle2 and halogenation of the aromatic ring of Phe4 showed highly increased opioid activities. Ligand 6 with good biological activities in vitro demonstrated potent in vivo antihyperalgesic and antiallodynic effects in the tail-flick assay.
PMCID: PMC3136578  PMID: 21128594
11.  Biological and Conformational Evaluation of Bifunctional Compounds for Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists Possessing Two Penicillamines 
Journal of medicinal chemistry  2010;53(15):5491-5501.
Neuropathic pain states and tolerance to opioids can result from system changes in the CNS, such as up-regulation of the NK1 receptor and substance P, which have anti-opioid effects in ascending or descending pain-signaling pathways. Bifunctional compounds, possessing both the NK1 antagonist pharmacophore and the opioid agonist pharmacophore with delta-selectivity, could counteract these system changes to have significant analgesic efficacy without undesirable side effects. As a result of the introduction of cyclic and topological constraints with penicillamines, 2 (Tyr-cyclo[D-Pen-Gly-Phe-Pen]-Pro-Leu-Trp-NH-[3′,5′-(CF3)2-Bzl]) was found as the best bifunctional compound with effective NK1 antagonist and potent opioid agonist activities, and 1400-fold delta-selectivity over the mu-receptor. The NMR structural analysis of 2 revealed that the relative positioning of the two connected pharmacophores as well as its cyclic and topological constraints might be responsible for its excellent bifunctional activities as well as its significant delta-opioid selectivity. Together with the observed high metabolic stability, 2 could be considered as a valuable research tool and possibly a promising candidate for a novel analgesic drug.
PMCID: PMC2943425  PMID: 20617791
bifunctional compound; opioid receptor agonists; neutokinin-1 receptor antagonists; NMR structure; membrane-compound interaction
12.  Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain 
It has been known that co-administration of morphine with either cholecystokinin(CCK) receptor or melanocortin (MC) receptor antagonists enhance morphine's analgesic efficacy by reducing serious side effects such as tolerance and addiction.1–4 Considering these synergistic effects, we have designed trivalent ligands in which all three different pharmacophores for opioid, CCK, and MC receptors are combined in such a way as to conserve their own topographical pharmacophore structures. These ligands, excluding the cyclic compound, were synthesized by solid phase synthesis using Rink-amide resin under microwave assistance in very high yields. These trivalent ligands bind to their respective receptors well demonstrating that the topographical pharmacophore structures for the three receptors were retained for receptor binding. Ligand 10 was a lead compound to show the best biological activities at all three receptors.
PMCID: PMC2917332  PMID: 20547453
13.  Synthesis and evaluation of new endomorphin-2 analogues containing (Z)-α,β-didehydro-phenylalanine (ΔZPhe) residues 
Journal of medicinal chemistry  2010;53(11):4550-4554.
New endomorphin-2 (EM-2) analogues incorporating (Z)-α,β-didehydro-phenylalanine (ΔZPhe) in place of the native phenylalanine in EM-2 are reported. Tyr-Pro-ΔZPhe-Phe-NH2 {[ΔZPhe3]EM-2} (1), Tyr-Pro-Phe-ΔZPhe-NH2 {[ΔZPhe4]EM-2} (2) and Tyr-Pro-ΔZPhe-ΔZPhe-NH2 {[ΔZPhe3,4]EM-2}(3) have been synthesized, their opioid receptor binding affinities and tissue bioassay activities were determined, and their conformational properties were examined. Compound 2 shows high µ opioid receptor selectivity and µ agonist activity comparable to that of the native peptide. The conformation adopted in solution and in the crystal by N-Boc-Tyr-Pro-ΔZPhe-Phe-NH2 (8) is reported.
PMCID: PMC2918392  PMID: 20476738
14.  Original Article A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer 
Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer.
Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n=19; imexon 200 or 280 mg/m2 intravenously (IV) over 30 minutes days 1–5, 15–19 and gemcitabine 800 or 1,000 mg/m2 IV over 30 minutes on days 1,8,15 every 28 days) or regimen B (n=86; imexon 280–1,300 mg/m2 IV over 30–60 minutes days 1, 8, and 15 and gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1, 8, and 15 every 28 days).
One hundred-five patients received 340 treatment cycles (median 2, range 1–16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half-life 69 minutes at the MTD and no alteration of gemcitabine pharmacokinetics.
The recommended phase II dose of imexon is 875 mg/m2 with gemcitabine 1,000 mg/m2. DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.
PMCID: PMC2873145  PMID: 19855966
gemcitabine; imexon; pancreatic cancer; phase I clinical trial
15.  The Biological Activity and Metabolic Stability of Peptidic Bifunctional Compounds That Are Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists with A Cystine Moiety 
Bioorganic & medicinal chemistry  2009;17(20):7337-7343.
In order to improve metabolic stability, a ring structure with a cystine moiety was introduced into TY027 (Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3’,5’-(CF3)2Bzl]), which is a lead compound of our developing bifunctional peptide possessing opioid agonist and NK1 antagonist activities. TY038 (Tyr-cyclo[D-Cys-Gly-Phe-Met-Pro-D-Cys]-Trp-NH-[3’,5’-(CF3)2Bzl]) was found as a highly selective δ opioid agonist over μ receptor in conventional tissue-based assays, together with an effective NK1 antagonist activity and good metabolic stability with more than 24 h half life in rat plasma.
PMCID: PMC2775479  PMID: 19762245
bifunctional compounds; disulfide bond; opioid agonists; neutokinin-1 antagonists; metabolic stability
16.  Synthesis and evaluation of new endomorphin analogues modified at the Pro2 residue 
Six new endomorphin analogues, incorporating constrained amino acids in place of native proline have been synthesized. Residues of (S)-azetidine-2-carboxylic acid (Aze), 3,4-didehydro-(S)-proline (Δ3Pro), azetidine-3-carboxylic acid (3Aze) and didehydro-alanine (ΔAla) have been used to prepare [Δ3Pro2]EM-2 (1), [Aze2]EM-1 (2), [Aze2]EM-2 (3), [3Aze2]EM-1 (4), [3Aze2]EM-2 (5) and [ΔAla2]EM-2 (6). Binding assays and functional bioactivities for μ- and δ-receptors are reported. The highest affinity, bioactivity and selectivity is shown by peptides 2 and 3 containing the Aze residue.
PMCID: PMC2737817  PMID: 19560919
azetidine carboxylic acids; 3,4-didehydro-(S)-proline; didehydro-alanine; endomorphins; μ-receptors
17.  Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain 
Bioorganic & medicinal chemistry  2009;17(14):5044-5053.
Acids 9 a–f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.
PMCID: PMC2759397  PMID: 19540763
18.  Solid-Phase Synthetic Strategy & Bioevaluation of a Labeled δ-Opioid Receptor Ligand Dmt-Tic-Lys for In Vivo Imaging 
Organic letters  2009;11(12):2479-2482.
A general solid-phase synthetic strategy is developed to prepare fluorescent and/or lanthanide labeled derivatives of the δ-opioid receptor (δOR) ligand H-Dmt-Tic-Lys(R)-OH. The high δ-OR affinity (Ki = 3 nM) and desirable in vivo characteristics of the Cy5 derivative 1 suggests its usefulness for structure-function studies, receptor localization and as a high-contrast non-invasive molecular marker for live imaging ex vivo or in vivo.
PMCID: PMC2756606  PMID: 19445485
19.  The Importance of Micelle-Bound States for the Bioactivities of Bifunctional Peptide Derivatives for δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists 
Journal of medicinal chemistry  2008;51(20):6334-6347.
In order to provide new insight into the determining factors of membrane-bound peptide conformation which might play an important role in peptide-receptor docking and further biological behaviors, the dodecylphosphocholine (DPC) micelle-bound conformations of bifunctional peptide derivatives of δ-preferring opioid agonists and NK1 antagonists (1: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3)2; 2: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3,5-Bzl(CF3)2; 3: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bzl) were determined based on 2D NMR studies. Although the differences in the primary sequence were limited to the C-terminus, the obtained NMR conformations were unexpectedly different for each compound. Moreover, their biological activities showed different trends in direct relation to the compound-specific conformations in DPC micelles. The important result is that not only were the NK1 antagonist activities different (the pharmacophore located at the C-terminus), but the opioid agonist activities (this pharmacophore was at the structurally preserved N-terminus) also were shifted, suggesting that a general conformational change in the bioactive state was induced due to relatively small and limited structural modifications.
PMCID: PMC2675940  PMID: 18821747
bifunctional peptides; analgesics; opioid induced tolerance; opioid receptor agonists; neurokinin-1 receptor antagonists; structure-activity relationships; NMR structure; DPC micelles; conformation; fluorine
20.  A Structure–Activity Relationship Study and Combinatorial Synthetic Approach of C-Terminal Modified Bifunctional Peptides That Are δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists 
Journal of medicinal chemistry  2008;51(5):1369-1376.
A series of bifunctional peptides with opioid agonist and substance P antagonist bioactivities were designed with the concept of overlapping pharmacophores. In this concept, the bifunctional peptides were expected to interact with each receptor separately in the spinal dorsal horn where both the opioid receptors and the NK1 receptors were found to be expressed, to show an enhanced analgesic effect, no opioid-induced tolerance, and to provide better compliance than coadministration of two drugs. Compounds were synthesized using a two-step combinatorial method for C-terminal modification. In the method, the protected C-terminal-free carboxyl peptide, Boc-Tyr(tBu)-d-Ala-Gly Phe-Pro-Leu-Trp(Boc)-OH, was synthesized as a shared intermediate using Fmoc solid phase chemistry on a 2-chlorotrityl resin. This intermediate was esterified or amidated in solution phase. The structure–activity relationships (SAR) showed that the C-terminus acted as not only a critical pharmacophore for the substance P antagonist activities, but as an address region for the opioid agonist pharmacophore that is structurally distant from the C-terminal. Among the peptides, H-Tyr-d-Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl (3) demonstrated high binding affinities at both δ and μ receptors (Ki = 10 and 0.65 nM, respectively) with efficient agonist functional activity in the mouse isolated vas deferens (MVD) and guinea pig isolated ileum (GPI) assays (IC50 = 50 and 13 nM, respectively). Compound 3 also showed a good antagonist activity in the GPI assay with substance P stimulation (Ke = 26 nM) and good affinity for the hNK1 receptor (Ki = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.
PMCID: PMC2737825  PMID: 18266313
21.  Structure-Activity Relationships of Bifunctional Cyclic Disulfide Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors 
Peptides  2008;29(8):1413-1423.
Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system, where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[D-Cys-Gly-Trp-Cys]-Asp-Phe-NH2) showed potent binding and agonist activities at δ and µ opioid receptors while displaying some binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.
PMCID: PMC2601673  PMID: 18502541
Multivalent Ligands; Bifunctional Peptides; Overlapping Pharmacophores; G-Protein Coupled Receptors; Pain; Tolerance; NMR Conformation
22.  Opioid and Melanocortin Receptors: Do They Have Opioid Overlapping Pharmacophores? 
Biopolymers  2008;90(3):433-438.
We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opioid receptor, 2,6-dimethyltyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), and a small molecule for the MC receptor, Tic-DPhe(p-Cl)-piperidin-4-yl-N-phenyl-propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the δ opioid receptor (Ki = 0.38 nM in binding assay, EC50 = 0.48 nM in GTP-γ-S binding assay, IC50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC50 = 2.3 μM) at the MC-3 receptor rather than at the MC-5 receptor. A study of the structure-activity relationships demonstrated that the residues in positions 2, 3, and the C-terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.
PMCID: PMC2693099  PMID: 17657709
opioid receptor; melanocortin receptor; anti-opioid effect; multi-target drug; overlapping pharmacophores; antinociception; side effect; Dmt-Tic; fentanyl
23.  Development of novel enkephalin analogues which have enhanced opioid activities at both μ and δ opioid receptors 
Journal of medicinal chemistry  2007;50(22):5528-5532.
Enkephalin analogues with an 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed μ and δ opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety showed very high binding affinities (0.4 nM) at μ and δ receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.
PMCID: PMC2678914  PMID: 17927164
24.  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
25.  Design, Synthesis, and Biological Evaluation of Novel Bifunctional C-Terminal-Modified Peptides for δ/μ Opioid Receptor Agonists and Neurokinin-1 Receptor Antagonists 
Journal of medicinal chemistry  2007;50(12):2779-2786.
A series of bifunctional peptides that act as agonists for δ and μ opioid receptors with δ selectivity and as antagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application as analgesics in various pain states. The peptides were characterized using radioligand binding assays and functional assays using cell membrane and animal tissue. Optimization was performed on the fifth residue which serves as an address moiety for both receptor recognitions. It had critical effects on both activities at δ/μ opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3)2 (5) and H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF3)2 (7) had excellent agonist activity for both δ opioid and μ opioid receptors and excellent antagonist activity for NK1 receptors. These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1 antagonist activities can be accomplished and may provide a new tool for treatment of chronic and several pain states.
PMCID: PMC2365895  PMID: 17516639

Results 1-25 (34)