A Bivalent Ligand (KDN-21) Reveals Spinal δ and κ Opioid Receptors Are Organized as Heterodimers That Give Rise to δ1 and κ2 Phenotypes. Selective Targeting of δ−κ Heterodimers

Bhushan, Rashmi G.; Sharma, Shiv K.; Xie, Zhihua; Daniels, David J.; Portoghese, Philip S.

doi:10.1021/jm0342358

Cited by 135 publications

(200 citation statements)

References 18 publications

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“…[103,117,186,[201][202][203][204][205][206][207] An illustration of this approach is the use small molecule dimer of GPCR ligand, which has been used to activate neutrophil chemotaxis. Neutrophils are attracted to sites of bacterial infection by byproducts of bacterial protein synthesis, such as N-formyl methionine-containing peptide fragments.…”

Section: 1b G-protein Coupled Receptors (Gpcrs)-gpcrsmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Section: 1b G-protein Coupled Receptors (Gpcrs)-gpcrsmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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“…5,6 Such ligands whose spacer is in the range of 18-21 atoms have pharmacological properties that are consistent with the activation or antagonism of heteromeric opioid receptors in vivo and in vitro. 7 Thus, bivalent ligands have been reported for targeting of heteromeric μ-κ, κ-δ, and μ-δ opioid receptors.…”

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confidence: 93%

“…Significantly, the spacer length for the presumed bridging of receptors is in the range of 16-21 atoms for these bivalent ligands, which is of sufficient length for cross-linking the receptor protomers in an oligomeric array. [5][6][7][8][9][10] Different pharmacological selectivity profiles upon intrathecal (i.t.) versus intracerebroventricular (i.c.v.)…”

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confidence: 99%

“…versus intracerebroventricular (i.c.v.) administration have been observed during the study with the bivalent ligand KDN-21 (1), 6 which has κ and δ opioid receptor antagonist pharmacophores tethered with a spacer. KDN-21 was characterized by substantially higher i.t.…”

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confidence: 99%

“…One possibility is that this arises as a consequence of allosterism between heteromeric κ-δ opioid receptors. 6,7,12 To investigate this further, ligand 6 was tested using the calcium release assay 19 on HEK-293 cells stably expressing μ, κ, δ, κ-δ, κ-μ, and μ-δ opioid receptors. These six cell lines also contained a transiently expressed chimeric G i iq protein, which stimulates the release of calcium upon activation.…”

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confidence: 99%

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A κ Opioid Pharmacophore Becomes a Spinally Selective κ-δ Agonist When Modified with a Basic Extender Arm

Tang

Yang

Lunzer

et al. 2010

ACS Med. Chem. Lett.

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We have explored the concept of a molecular extender arm attached to a κ opioid agonist pharmacophore 3 (ICI-199,441) in an effort to potentially interact with a complementary group on a neighboring opioid receptor. The molecular arm containing a terminal amine group was lengthened incrementally from 11 up to 18 atoms. Increasing the number of atoms in the arm produced virtually no change in the mouse intracerebroventricular (i.c.v.) antinociceptive potency. In contrast, the intrathecal (i.t.) potency of 6 (KDA-16) with a 16-atom arm was dramatically increased, as reflected by its antinociceptive i.c.v./i.t. ED 50 ratio of ∼130. Further lengthening led to a decreased ED 50 ratio. In vivo selective antagonist studies of KDA-16 revealed that κ and δ opioid receptors were responsible for the greatly enhanced i.t. potency. Calcium release experiments in HEK-293 cells suggested that KDA-16 selectively activate κ-δ heteromers. These data are consistent with the reported possible presence of heteromeric κ-δ opioid receptors in mouse spinal cord but not in the brain. The use of a molecular extender arm may be useful for developing spinally selective analgesics.

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Synthetische multivalente Liganden als Sonden für die Signaltransduktion

2006

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Zelloberflächenrezeptoren nehmen Informationen aus der extrazellulären Umgebung auf und stimmen die intrazellulären Reaktionen darauf ab. Viele dieser Rezeptoren agieren nicht einzeln, sondern als Teil von dimeren oder oligomeren Komplexen. Die funktionelle Kopplung mehrerer Rezeptoren verleiht den Signaltransduktionswegen möglicherweise die Empfindlichkeit, die für die Regulation zellulärer Reaktionen erforderlich ist. Außerdem können Multirezeptor‐Signalkomplexe ansonsten überlappende Signalkaskaden räumlich trennen. Die Mechanismen, das Ausmaß und die Konsequenzen der Colokalisation und die Kommunikation zwischen den Rezeptoren sind noch unklar, doch synthetische Verbindungen können dabei helfen, die Rolle der Rezeptorassoziationen bei der Signaltransduktion zu ermitteln. Solche multivalenten Liganden können Bindestellen verschiedener Größe, Form, Valenz, Orientierung und räumlicher Anordnung enthalten. Der Schwerpunkt dieses Aufsatzes liegt auf dem Einsatz synthetischer multivalenter Liganden, um die Rezeptorfunktion zu charakterisieren.

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A Bivalent Ligand (KDN-21) Reveals Spinal δ and κ Opioid Receptors Are Organized as Heterodimers That Give Rise to δ₁ and κ₂ Phenotypes. Selective Targeting of δ−κ Heterodimers

Cited by 135 publications

References 18 publications

Synthetic Multivalent Ligands as Probes of Signal Transduction

Synthetic Multivalent Ligands as Probes of Signal Transduction

A κ Opioid Pharmacophore Becomes a Spinally Selective κ-δ Agonist When Modified with a Basic Extender Arm

Synthetische multivalente Liganden als Sonden für die Signaltransduktion

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