Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

Daniels, David J.; Lenard, Natalie R.; Etienne, Chris; Law, Ping Yee; Roerig, Sandra C.; Portoghese, Philip S.

doi:10.1073/pnas.0506627102

Cited by 268 publications

(331 citation statements)

References 36 publications

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“…Thus, the oligomerization process is of potential great importance for neuropsychopharmacology and the GPCR complexes have become exciting new targets for the development of novel therapeutic strategies in CNS diseases (see Guidolin et al, 2015;Fuxe and BorrotoEscuela, 2016;Borroto-Escuela et al, 2017;Farran 2017). The main focus of this research line is presently on the identification or development of new ligands specific for the receptor complexes (Bhushan et al, 2004;Daniels et al, 2005). However, the identification of receptor complexes that are typically expressed in human nerve tissues and the structural or biochemical changes they undergo in pathologic conditions (Zalewska et al, 2014) should represent further lines of future pharmacologic research.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, such protocols when compared to the traditional ones often appear able to reduce collateral effects (Le Naour et al, 2014). Of particular interest were recent advances leading to the development of receptor complex-specific ligands (Bhushan et al, 2004;Daniels et al, 2005) that could lead to the identification of new tools for pharmacologic intervention.…”

Section: Introductionmentioning

confidence: 99%

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G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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Abstract:The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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“…8 Physical interactions between δ-and μ-opioid receptors were suggested to modulate μ-mediated tolerance and dependence 9 when the development of bivalent ligands was constituted as a useful approach to investigate changes in receptor properties as a consequence to dimerization. 10,11 Heterodimerization is also a highly relevant phenomenon for dopamine receptor mediated signaling. 12,13 Demonstrating the development of a new complex with enhanced functional activity through hetero-oligomerization, the physical interaction between the dopamine D 2L and the somatostatin SST5 receptor was investigated via radioligand binding studies, functional assays, and FRET microscopy.…”

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confidence: 99%

Cross-Receptor Interactions between Dopamine D_2L and Neurotensin NTS₁ Receptors Modulate Binding Affinities of Dopaminergics

Koschatzky

Tschammer

Gmeiner

2011

ACS Chem. Neurosci.

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T he ability to form spatial complexes allowing molecular interactions between receptor protomers facilitates cooperative effects and tissue specific control of neuronal activity. Thus, heterodimerization is discussed as an integral feature of G-protein coupled receptor (GPCR) mediated signal transduction. 1À3 Intramembrane receptorÀreceptor interactions of associated protomers may modify binding and activating properties of GPCR ligands. 4À7 Using F€ orster resonance energy transfer (FRET) technique, a recent study on the interactions between R 2A -adrenergic and μ-opioid receptors demonstrated a transinhibitory effect between the protomers. In detail, morphine binding to the μ-opioid receptor triggered the conformational changes in the norepinephrine-occupied R 2A -adrenergic receptor leading to the inhibition of its signaling. 8 Physical interactions between δ-and μ-opioid receptors were suggested to modulate μ-mediated tolerance and dependence 9 when the development of bivalent ligands was constituted as a useful approach to investigate changes in receptor properties as a consequence to dimerization. 10,11 Heterodimerization is also a highly relevant phenomenon for dopamine receptor mediated signaling. 12,13 Demonstrating the development of a new complex with enhanced functional activity through hetero-oligomerization, the physical interaction between the dopamine D 2L and the somatostatin SST5 receptor was investigated via radioligand binding studies, functional assays, and FRET microscopy. 14 The heterooligomerization of D 2L and SST5, known for their colocalization in the central nervous system (CNS), led to a synergistic effect on binding and signaling as molecular cross-talk and the correlation between activated receptor function and oligomerization was stressed.Dopaminergic systems have been also described to functionally interact with the neuromodulatory peptide neurotensin (NT, pE-L-Y-E-N-K-P-R-R-P-Y-I-L) 15 which is suggested to play a role in the pathophysiology of brain diseases including schizophrenia, Parkinson's disease. and Morbus Alzheimer. 16À18 Thus, neurotensin was shown to negatively alter binding affinity of the dopamine receptor agonist [ 3 H]N-n-propyl-nor-apomorphine in specific brain areas. 19À25 However, biomolecular interactions and a putative heteromer formation between dopamine receptors and neurotensin receptors have not been investigated yet.Employing fluorescence detected coimmunoprecipitation and radioligand binding experiments, we herein demonstrate that coexpression of dopamine D 2L receptor and the neurotensin receptor subtype NTS 1 in human embryonic kidney cells (HEK293 cells) leads to physical interaction at a molecular level. In this in vitro system, a trans-inhibitory effect on the agonist binding affinity of D 2 was observed in the presence of neurotensin. A biochemical fingerprint 26 of the D 2L -NTS 1 heteromer was explored by investigating the effect of both neurotensin and NTS 1 on the D 2 receptor binding properties of different ABSTRACT: Dopaminergic systems ...

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“…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.)…”

mentioning

confidence: 99%

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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Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

Abstract: antinociception ͉ heterodimers

Cited by 268 publications

References 36 publications

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Cross-Receptor Interactions between Dopamine D_2L and Neurotensin NTS₁ Receptors Modulate Binding Affinities of Dopaminergics

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

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Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

Abstract: antinociception ͉ heterodimers

Cited by 268 publications

References 36 publications

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Cross-Receptor Interactions between Dopamine D2L and Neurotensin NTS1 Receptors Modulate Binding Affinities of Dopaminergics

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

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Cross-Receptor Interactions between Dopamine D_2L and Neurotensin NTS₁ Receptors Modulate Binding Affinities of Dopaminergics