Synthesis and Biological Activities of Cyclic Lanthionine Enkephalin Analogues: δ-Opioid Receptor Selective Ligands (original) (raw)
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Development of Potent μ and δ Opioid Agonists with High Lipophilicity
Journal of Medicinal Chemistry, 2011
An SAR study on the Dmt-substituted enkephalin-like tetrapeptide with a N-phenyl-N-piperidin-4yl 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-Nle 2 and halogenation of the aromatic ring of Phe 4 showed highly increased opioid activities. Ligand 6 with good biological activities in vitro demonstrated potent in vivo antihyperalgesic and antiallodynic effects in the tailflick assay.
Cyclic Enkephalin Analogues with Exceptional Potency and Selectivity for δ-Opioid Receptors 1
Journal of Medicinal Chemistry, 1997
Superpotent and highly delta-opioid receptor selective cyclic peptides of the general formula H-Tyr-c[D-Pen-Gly-Phe(p-X)-Pen]-Phe-OH (where X = hydrogen or halogen) have been synthesized. In the binding assays the most selective and most potent compound is the p-bromophenyl-alanine-4 analogue (IC50 value = 0.19 nM, selectivity ratio = 21,000 for delta vs mu). In the GPI and MVD bioassays the most selective and most potent analogue is the p-fluoro-substituted analogue Tyr-[D-Pen-Gly-Phe(p-F)-Pen]-Phe-OH. In the MVD assay it has an exceptionally low IC50 value of 0.016 nM and a delta vs mu selectivity ratio of 45,000.
Cyclic Enkephalin Analogues with Exceptional Potency and Selectivity for δ-Opioid Receptors
Journal of Medicinal Chemistry, 1997
Superpotent and highly δ-opioid receptor selective cyclic peptides of the general formula H-Tyrc[D-Pen-Gly-Phe(p-X)-Pen]-Phe-OH (where X) hydrogen or halogen) have been synthesized. In the binding assays the most selective and most potent compound is the p-bromophenylalanine-4 analogue (IC 50 value) 0.19 nM, selectivity ratio) 21 000 for δ vs µ). In the GPI and MVD bioassays the most selective and most potent analogue is the p-fluoro-substituted analogue Tyr-[D-Pen-Gly-Phe(p-F)-Pen]-Phe-OH. In the MVD assay it has an exceptionally low IC 50 value of 0.016 nM and a δ vs µ selectivity ratio of 45 000.
Journal of Heterocyclic Chemistry, 2016
Several studies have suggested functional association between μ-opioid and δ-opioid receptors and showed that μ-activity could be modulated by δ-ligands. The general conclusion is that agonists for the δ-receptor can enhance the analgesic potency and efficacy of μ-agonists. Our preliminary investigations demonstrate that new bivalent ligands constructed from the μ-agonist fentanyl and the δ-agonist enkephalin-like peptides are promising entities for creation of new analgesics with reduced side effects for treatment of neuropathic pain. A new superposition of the mentioned pharmacophores led to novel μ-bivalent/δ-bivalent compounds that demonstrate both μ-opioid and δ-opioid receptor agonist activity and high efficacy in anti-inflammatory and neuropathic pain models with the potential of reduced unwanted side effects.
Pharmacological profiles of selective non-peptidic δ opioid receptor ligands
Molecular Brain Research, 2000
Several non-peptidic opioids have been synthesized recently as part of a program to develop selective d receptor agonists. In this study, the affinities of a set of compounds for cloned d and m opioid receptors expressed in HEK 293 cell lines were determined by competition 3 analysis of [ H]bremazocine binding to membrane preparations. All compounds studied exhibited high affinity and selectivity, with apparent dissociation constants in the range of 0.6-1.7 nM for the d opioid receptor and 240-1165 nM for the m opioid receptor. We next sought to determine which domain of the d receptor was critical for mediating the highly selective binding by analysis of ligand affinities for m / d receptor chimeras. Receptor binding profiles suggested that a critical site of receptor / ligand interaction was located between transmembrane domain 5 (TM5) and TM7 of the d receptor. Substitution of tryptophan 284, located at the extracellular surface of TM6, with lysine, which is found at the equivalent position in the m opioid receptor, led to a spectrum of effects on affinities, depending on the ligand tested. Affinities of SB 219825 and SB 222941 were particularly sensitive to the substitution, displaying a 50-fold and 70-fold decrease in affinity, respectively. Activities of the d receptor-selective agonists were tested in two functional assays. Brief exposure of HEK 293 cells expressing d opioid receptors with selective ligands induced phosphorylation of MAP kinase, although the non-peptidic ligands were less efficacious than the enkephalin derivative DADL (Tyr-D-Ala-Gly-Phe-D-Leu). Similarly, chronic exposure of HEK 293 cells expressing d opioid receptors with selective, non-peptidic ligands, with the exception of SB 206848, caused receptor downregulation, however, the SB compounds were less efficacious than DADL.
Cyclic enkephalin analogs with exceptional potency at peripheral .delta. opioid receptors
Journal of Medicinal Chemistry, 1994
A series of super potent and delta-opioid-receptor-selective cyclic hexapeptides of the general formula [formula: see text] (where X is hydrogen or halogen) has been synthesized. The unsubstituted hexapeptide formula; see text: [Phe6]DPLCE) has extremely high potency at peripheral delta opioid receptors (IC50 value in the MVD assay is 0.016 nM) and in bioassays is the most selective compound in this series. The introduction of halogens in the phenyl ring of phenylalanine at position 4 led to significant changes in the selectivity and affinities at peripheral and central opioid receptors. In the binding studies, the most potent compound is the p-fluoro analog, whereas the most selective analog is the p-iodo-substituted peptide.
Journal of Medicinal Chemistry, 2008
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 structureactivity 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 (K i = 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 (IC 50 = 50 and 13 nM, respectively). Compound 3 also showed a good antagonist activity in the GPI assay with substance P stimulation (K e = 26 nM) and good affinity for the hNK1 receptor (K i = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.
A Novel µ-Opioid Receptor Ligand with High In Vitro and In Vivo Agonist Efficacy
Current Medicinal Chemistry, 2012
The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as theopioid receptor (MOR) selective agonist peptide [D-Ala 2 ,N-Me-Phe 4 ,Gly-ol 5 ]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM, similarly to DAMGO. The Emax values (%) were 99.10, 36.87, 42. 51 and 96.99 for 14-O-MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-O-MeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was /μ=269 and /μ= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14-O-MeM6SU was the most potent. Our results showed that, introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax).
2007
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-Npiperidin-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.