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1.  Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain 
Life sciences  2013;93(0):1010-1016.
Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids has highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors.
Aims
Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors.
Main Methods
Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats.
Key findings
RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment.
Significance
This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.
doi:10.1016/j.lfs.2013.09.016
PMCID: PMC3962292  PMID: 24084045
chronic pain; allodynia; hyperalgesia; inflammatory; mice; rat; fentanyl; mu opioid; delta opioid; spinal nerve ligation; formalin flinch; naloxone
2.  Discovery of Amphipathic Dynorphin A Analogues to Inhibit the Neuroexcitatory Effects of Dynorphin A through Bradykinin Receptors in the Spinal Cord 
We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well known inhibitory effect of opioid receptors. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, but allowed us to discover a potential neuroexcitatory target. Well known BR ligands, BK, DALKD, and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure-activity relationship (SAR) study at the rat brain BRs was performed and as a result, a new key structural feature of Dyn A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg7]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn A’s biological activity, is not necessary, and that a type I β-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesic effects and motor impairment in in vivo assays using naïve rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A, which are likely to be mediated by BRs in the spinal cord.
doi:10.1021/ja501677q
PMCID: PMC4021566  PMID: 24742335
pathological chronic pain states; hyperalgesia; dynorphin A; bradykinin receptor recognition; non-opioid; amphipathic pharmacophore
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.
doi:10.1021/ml400115n
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.
doi:10.1021/ml400115n
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.
doi:10.1016/j.bmcl.2013.03.065
PMCID: PMC3942532  PMID: 23623418
Opioid peptide; Dynorphine analog; Bivalent ligand; Fentanyl; Analgesic
6.  Novel peptide ligands with dual acting pharmacophores designed for the pathophysiology of neuropathic pain 
Brain research  2011;1395:1-11.
The conventional design of high affinity drugs targeted to a single molecule has not resulted in clinically useful therapies for pain relief. Recent reviews have suggested that newly designed analgesic drugs should incorporate multiple targets. The distributions of cholecystokinin (CCK) and CCK receptors in the central nervous system (CNS) overlap significantly with endogenous opioid systems and can be dually targeted. CCK has been shown to act as an endogenous “anti-analgesic” peptide and neuropathic pain conditions promote endogenous CCK release in CNS regions of pain modulation. Administration of CCK into nuclei of the rostral ventromedial medulla induces pronociceptive behaviors in rats. RSA 504 and RSA 601 are novel bifunctional compounds developed to target neuropathic pain by simultaneously acting as agonists at two distinct opioid receptors and antagonizing CCK receptors in the CNS. RSA 504 and RSA 601 demonstrate agonist activity in vitro and antihypersensitivity to mechanical and thermal stimuli in vivo using the spinal nerve ligation model of neuropathic pain. Intrathecal administration of RSA 504 and RSA 601 did not demonstrate antinociceptive tolerance over 7 days of administration and did not display motor impairment or sedation using a rotarod. These are the first behavioral studies that demonstrate how multi-targeted molecule design can address the pathology of neuropathic pain. These compounds with δ and μ opioid agonist activity and CCK antagonist activity within one molecule offer a novel approach with efficacy for neuropathic pain while lacking the side effects typically caused by conventional opioid therapies.
doi:10.1016/j.brainres.2011.04.024
PMCID: PMC3105124  PMID: 21550594
neuropathic pain; spinal nerve ligation; cholecystokinin; opioids
7.  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.
doi:10.1021/jm100982d
PMCID: PMC3136578  PMID: 21128594
8.  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.
doi:10.1016/j.bmcl.2010.05.078
PMCID: PMC2917332  PMID: 20547453
9.  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.
doi:10.1016/j.peptides.2008.03.022
PMCID: PMC2601673  PMID: 18502541
Multivalent Ligands; Bifunctional Peptides; Overlapping Pharmacophores; G-Protein Coupled Receptors; Pain; Tolerance; NMR Conformation
10.  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.
doi:10.1002/bip.20814
PMCID: PMC2693099  PMID: 17657709
opioid receptor; melanocortin receptor; anti-opioid effect; multi-target drug; overlapping pharmacophores; antinociception; side effect; Dmt-Tic; fentanyl
11.  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.
doi:10.1021/jm061465o
PMCID: PMC2678914  PMID: 17927164
12.  Synthesis of a novel benzyl-octahydropyrazino[1,2-a]pyrimidin-6-one derivative as a convenient internal bicyclic peptidomimetic 
Tetrahedron letters  2008;49(14):2316-2319.
A substituted hydropyrazino[1,2-a]pyrimidin-6-one derivative was synthesized stereoselectively via the intramolecular N-acyliminium ion cyclization between an amide nitrogen and an Nα-acetal derived from Cbz-protected aminopropyl-phenylalaninamide in very good yields. The formation of a single diastereomer is due to the low energy chairlike conformation of its bicyclic structure. This methodology provides a convenient tool to build internal bicyclic peptidomimetics.
doi:10.1016/j.tetlet.2008.01.137
PMCID: PMC2390882  PMID: 19340283
internal bicyclic peptidomimetics; N-acylimnium ion cyclization; acetals
13.  Partial Retro–Inverso, Retro, and Inverso Modifications of Hydrazide Linked Bifunctional Peptides for Opioid and Cholecystokinin (CCK) Receptors 
Journal of medicinal chemistry  2007;50(1):165-168.
Partially modified retro–inverso, retro, and inverso isomers of hydrazide linked bifunctional peptides were designed, synthesized, and evaluated for bioactivities at δ/μ opioid receptors and CCK-1/CCK-2 receptors. All modifications of the CCK pharmacophore moiety affected bioactivities for the CCK-1 and CCK-2 receptors (up to 180-fold increase in the binding affinity with higher selectivity) and for the δ and μ opioid receptors. The results indicate that the opioid and CCK pharmacophores in one molecule interact with each other to induce topographical changes for both pharmacophores.
doi:10.1021/jm061268p
PMCID: PMC2365893  PMID: 17201419
14.  Understanding the structural requirements of 4-anilidopiperidine analogues for biological activities at μ and δ opioid receptors 
New 4-anilidopiperidine analogues in which the phenethyl group of fentanyl was replaced by several aromatic ring-contained amino acids (or acids) were synthesized to study the biological effect of the substituents on μ and δ opioid receptor interactions. These analogues showed broad (47 nM–76 μM) but selective (up to 17-fold) binding affinities at the μ opioid receptor over the δ opioid receptor, as predicted from the message-address concept.
doi:10.1016/j.bmcl.2007.01.114
PMCID: PMC2274923  PMID: 17329100
4-Anilidopiperidine analogues; Fentanyl; Dmt-Tic; Opioid receptors; Analgesic effects
15.  New Paradigms and Tools in Drug Design for Pain and Addiction 
The AAPS journal  2006;8(3):E450-E460.
New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at μ and δ opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in G-protein coupled receptors (GPCRs) as illustrated by the δ opioid receptor.
doi:10.1208/aapsj080353
PMCID: PMC1764851  PMID: 17025262
drug design; neuropathic pain; bifunctional ligands; plasmon waveguide resonance spectroscopy; GPCRs; opioid receptors; cholecystokinin receptors
16.  Design and Synthesis of Novel Hydrazide-Linked Bifunctional Peptides as δ/μ Opioid Receptor Agonists and CCK-1/CCK-2 Receptor Antagonists 
Journal of medicinal chemistry  2006;49(5):1773-1780.
A series of hydrazide-linked bifunctional peptides designed to act as agonists for δ /μ opioid receptors and antagonists for CCK-1/CCK-2 receptors was prepared and tested for binding to both opioid and CCK receptors and in functional assays. SAR studies in the CCK region examined the structural requirements for the side chain groups at positions 1′, 2′, and 4′ and for the N-terminal protecting group, which are related to interactions not only with CCK, but also with opioid receptors. Most peptide ligands that showed high binding affinities (0.1–10 nM) for both δ and μ opioid receptors generally showed lower binding affinities (micromolar range) at CCK-1 and CCK-2 receptors, but were potent CCK receptor antagonists in the GPI/LMMP assay (up to Ke = 6.5 nM). The results indicate that it is reasonable to design chimeric bifunctional peptide ligands for different G-protein coupled receptors in a single molecule.
doi:10.1021/jm05085
PMCID: PMC1614704  PMID: 16509592
17.  Structure–Activity Relationships of Bifunctional Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors 
Journal of medicinal chemistry  2006;49(10):2868-2875.
Cholecystokinin (CCK) has been identified as a pronociceptive endogenous peptide which also possesses antiopioid actions. CCK may be upregulated in conditions of chronic pain or during sustained morphine administration resulting in attenuation of opioid-mediated pain relief. These complex interactions between opioids and endogenous CCK receptor systems have suggested the need for a new paradigm in drug design for some states of chronic pain. In these circumstances the rational design of potential drugs for the treatment of these conditions must be based on one ligand for multiple targets. We have designed a single peptide which can interact with δ and μ opioid receptors as agonists and with CCK receptors as antagonists. The ligands were designed based on a model of overlapping pharmacophores of opioid and CCK peptide ligands, which incorporates opioid pharmacophores at the N-terminal and CCK tetrapeptide pharmacophores at the C-terminal of the designed ligands. We measured binding and activities of our bifunctional peptides at opioid and CCK receptors. Compound 11 (Tyr-d-Ala-Gly-d-Trp-NMeNle-Asp-Phe-NH2) demonstrated opioid agonist properties at δ and μ receptors (IC50 = 63 ± 27 nM and 150 ± 65 nM, respectively in MVD and GPI tissue assays) and high binding affinity at CCK-1 and CCK-2 receptors (Ki = 320 and 1.5 nM, respectively). Compound 9 (Tyr-d-Nle-Gly-Trp-Nle-Asp-Phe-NH2) displayed potent agonist activity at δ and μ receptors (IC50 = 23 ±10 nM and 210 ± 52 nM, respectively in MVD and GPI tissue assays), with a balanced binding affinity for CCK-1 and CCK-2 receptors (Ki = 9.6 and 15 nM, respectively). These results provide evidence supporting the concept that opioid and CCK receptors have overlapping pharmacophores required for binding affinity and biological activity and that designing overlapping pharmacophores of two peptides into a single peptide is a valid drug design approach.
doi:10.1021/jm050921q
PMCID: PMC1484468  PMID: 16686530
18.  New paradigms and tools in drug design for pain and addiction 
The AAPS Journal  2006;8(3):E450-E460.
New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at μ and σ opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in g-protein coupled receptors (GPCRs) as illustrated by the δ opioid receptor.
doi:10.1208/aapsj080353
PMCID: PMC1764851  PMID: 17025262
drug design; neuropathic pain; bifunctional ligands; plasmon waveguide resonance spectroscopy; GPCRs; opioid receptors; cholecystokinin receptors

Results 1-18 (18)