New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

Plobeck, Niklas; Delorme, Daniel; Wei, Zhongyong; Yang, Hua; Zhou, Fei; Schwarz, Peter E. H.; Gawell, Lars; Gagnon, Helene; Pelcman, Benjamin; Schmidt, Ralf; Yue, Shi Yi; Walpole, Christopher; Brown, W. A.; Zhou, Edward; Labarre, Maryse; Payza, Kemal; St-Onge, Stéphane; Kamassah, Augustus; Morin, Pierre-Emmanuel; Projean, Denis; Ducharme, Julie; Roberts, Edward

doi:10.1021/jm000228x

Cited by 116 publications

(65 citation statements)

References 22 publications

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“…Data are presented as means Ϯ SEM. sections adjacent to those used for in situ hybridization were processed for receptor autoradiography using [ 125 I]-deltorphin-II ([ 125 I]-DLT-II) (Plobeck et al, 2000). The peptide (BACHEM Bioscience, King of Prussia, PA) was iodinated according to the chloramine T method as described previously (Fraser et al, 1999) (specific activity, 2200 Ci/mmol).…”

Section: Light Microscopic Immunolabeling Of Rat Brain Sectionsmentioning

confidence: 99%

Morphine-Induced Changes in δ Opioid Receptor Trafficking Are Linked to Somatosensory Processing in the Rat Spinal Cord

et al. 2004

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An in vivo fluorescent deltorphin (Fluo-DLT) internalization assay was used to assess the distribution and regulation of pharmacologically available ␦ opioid receptors (␦ORs) in the rat lumbar (L4 -5) spinal cord. Under basal conditions, intrathecal injection of Fluo-DLT resulted in the labeling of numerous ␦OR-internalizing neurons throughout dorsal and ventral horns. The distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent with that of ␦OR-expressing neurons, as revealed by in situ hybridization and immunohistochemistry, suggesting that a large proportion of these cells was responsive to intrathecally administered ␦OR agonists. Pretreatment of rats with morphine for 48 hr resulted in a selective increase in Fluo-DLT-labeled perikaryal profiles within the dorsal horn. These changes were not accompanied by corresponding augmentations in either ␦OR mRNA or 125 I-deltorphin-II binding levels, suggesting that they were attributable to higher densities of cell surface ␦OR available for internalization rather than to enhanced production of the receptor. Unilateral dorsal rhizotomy also resulted in increased Fluo-DLT internalization in the ipsilateral dorsal horn when compared with the side contralateral to the deafferentation or to non-deafferented controls, suggesting that ␦OR trafficking in dorsal horn neurons may be regulated by afferent inputs. Furthermore, morphine treatment no longer increased Fluo-DLT internalization on either side of the spinal cord after unilateral dorsal rhizotomy, indicating that OR-induced changes in the cell surface availability of ␦OR depend on the integrity of primary afferent inputs. Together, these results suggest that regulation of ␦OR responsiveness through OR activation in this region is linked to somatosensory information processing.

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Section: Light Microscopic Immunolabeling Of Rat Brain Sectionsmentioning

confidence: 99%

Morphine-Induced Changes in δ Opioid Receptor Trafficking Are Linked to Somatosensory Processing in the Rat Spinal Cord

et al. 2004

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“…125 I]-DELT-II (Plobeck et al, 2000; iodination was performed using the chloramine T method; specific activity was considered to be 2000 Ci/mmol, the theoretical value). Sections were preincubated for 30 minutes at room temperature in 50 mM Tris-HCl, 120 mM NaCl, and 1 mM MgCl 2 buffer (pH 7.4) and then incubated for 60 minutes at room temperature in the same buffer containing 0.5% bovine serum albumin (BSA), 0.1 mM Bestatin, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), and 40 pM […”

Section: I]-delt-ii Binding Sitesmentioning

confidence: 99%

Phylogenetic changes in the expression of delta opioid receptors in spinal cord and dorsal root ganglia

Mennicken

Zhang

Hoffert

et al. 2003

J of Comparative Neurology

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To assess the validity of rodent models for investigating the role of delta opioid receptors (DOR) in analgesia, the distribution of DOR binding and mRNA were compared between rodent and primate spinal cord and dorsal root ganglia (DRG), using receptor autoradiography and in situ hybridization, respectively. In mouse and rat spinal cord, [(125)I]-deltorphin-labeled DOR binding sites were detected throughout the gray matter. In contrast, in primate and particularly in human spinal cord, DOR binding was mainly present in laminae I-II, with little to no binding in deeper layers. Accordingly, in rodent spinal cord, DOR mRNA was expressed by a large number of neurons distributed throughout the ventral and dorsal horns, whereas in the primate, DOR expression was significantly lower, as evidenced by a moderate number of labeled cells throughout the gray matter in monkey and by only few labeled cells in human, mainly in Clarke's column and lamina IX. Major species differences in DOR expression were also observed in primary afferent cells bodies. In rat DRG, intense DOR mRNA hybridization was primarily observed over large ganglion cells immunopositive for neurofilament 200. In contrast, in monkey and human DRG, DOR mRNA was primarily detected over small and medium-sized ganglion cells. These results demonstrate major differences in the expression and distribution of DOR in the spinal cord and DRG between mammalian species. Specifically, they point to a progressive specialization of DOR toward the regulation of primary somatosensory, namely nociceptive, inputs during phylogeny and suggest that the effects of DOR agonists in rodents may not be entirely predictive of their action in humans.

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“…This GPCR protein is located in the central nervous system and to a lesser extent in peripheral tissues [19]. CB-1 antagonists and inverse agonists have been reported to influence memory as well as appetite control and smoking cessation which makes this receptor an attractive drug target for therapeutic intervention [11].…”

Section: Full Papermentioning

confidence: 99%

Identification of novel cannabinoid receptor ligands via evolutionary de novo design and rapid parallel synthesis

et al. 2004

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A rapid entry to novel and patentable cannabinoid receptor (CB-1) ligands has been identified using computer-based de novo design in combination with parallel synthesis. Small targeted compound arrays were readily prepared from the designs yielding active hit rates of 6% and 10%, respectively. This represents a hit rate enrichment of up to two orders of magnitude compared with corporate compound collections and is the first report of the application of the TOPAS algorithm for the de novo design of GPCR ligands.G-protein coupled receptors (GPCRs) are by far the largest single group of targets within pharmaceutical research today [1]. Not only are they involved in various pharmacological pathways but are also implicated in many different therapeutic indications ranging from infectious and metabolic diseases to CNS disorders. Within the GPCR protein family, extremely limited biostructural information is available due to inherent difficulties arising from large protein size and high lipophilicity. This makes isolation and biostructural characterization of GPCRs a major challenge currently. Rational drug design based upon structural homology is challenging due to the large size and complexity of the target proteins. This requires both computationally intensive and lengthy molecular dynamics refinement as well as detailed mutagenesis efforts to produce an accurate, validated and predictive model due to our limited understanding of ligandreceptor interaction patterns in GPCRs [2]. Successful examples of this approach have been reported ever toward designing novel cannabinoid receptor ligands by structurebased methods which rely on receptor binding-site models [3]. However in general, ligand discovery efforts are commonly initiated based on a high throughput random screening (HTS) program placing pressure on assay development, compound library management and the corresponding logistics, as key bottlenecks. Since the majority of −drugable× targets within pharmacological research belong to this class of proteins it is clear that there is a need for novel technologies which complement classical HTS approaches [4]. Herein we describe the application of an iterative ligand-based library design strategy for the production of small focused compound collections with the goal of generating novel and patentable ligands for the GPCR cannabinoid subtype receptor 1 (CB-1).With the advent of combinatorial chemistry and ultra-HTS, the generation of large compound libraries has become commonplace within the drug discovery industry. Initially, library designs were simply based on chemical feasibility rather than target relevant criteria. Combinatorial chemistry libraries consisted of unpurified mixtures of compounds submitted directly for biological testing, however due to the high false positive and low validated hit rates, the trend is now increasingly towards purified discretes. More recently, a shift from random compound libraries to sophisticated maximally diverse compound collections and targeted compound arrays was favoured [5]. W...

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New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

Cited by 116 publications

References 22 publications

Morphine-Induced Changes in δ Opioid Receptor Trafficking Are Linked to Somatosensory Processing in the Rat Spinal Cord

Morphine-Induced Changes in δ Opioid Receptor Trafficking Are Linked to Somatosensory Processing in the Rat Spinal Cord

Phylogenetic changes in the expression of delta opioid receptors in spinal cord and dorsal root ganglia

Identification of novel cannabinoid receptor ligands via evolutionary de novo design and rapid parallel synthesis

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