Agonistic and Antagonistic Bivalent Ligands for Serotonin and Dopamine Receptors Including their Transporters

Decker, Michael; Lehmann, Jochen

doi:10.2174/156802607779941297

Cited by 21 publications

(8 citation statements)

References 37 publications

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“…These ligands are comprised of two pharmacophores covalently tethered via a suitable spacer that are hypothesized to interact with a binding site on each receptor in the dimer pair . Bivalent ligands have been synthesized to examine various neurotransmitter receptor systems, including 5-HT receptors − such as the 5-HT 4 R , and the 5-HT 1B R. − Here, we characterize homobivalent ligands with the pharmacophore of the piperidine M100907 that may serve as future tools for pharmacologically probing 5-HT 2A R:5-HT 2A R biology. The active (+)-isomer of M100907 [(+)-M100907; compound 1 (Figure )] binds the 5-HT 2A R with a high affinity and has a >100-fold selectivity over the 5-HT 2B R and 5-HT 2C R. , The pharmacology of M100907 has been demonstrated in a wide diversity of in vitro , and in vivo ,,,, studies.…”

Section: Introductionmentioning

confidence: 99%

Novel Bivalent 5-HT_2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

Soto

Shashack

Fox

et al. 2017

ACS Chem. Neurosci.

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The 5-HT receptor (5-HTR) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HTR:5-HTR homodimer in these disorders are necessary. We chemically modified the selective 5-HTR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HTR:5-HTR homodimer function. We tested these molecules for 5-HTR antagonist activity in a cell line stably expressing the functional 5-HTR and quantified a downstream signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK), in comparison to in vivo efficacy of altering spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length, with the intermediate linker lengths being the most potent. The K values for the binding of bivalent ligands to 5-HTR were only slightly lower than the values for the parent (+)-M100907 compound, but significant selectivity for 5-HTR over 5-HTR or 5-HTR binding was retained. In addition, the 11-atom-linked bivalent 5-HTR antagonist (2 mg/kg, intraperitoneally) demonstrated efficacy on par with that of (+)-M100907 in inhibiting cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HTR antagonist ligands will serve as useful in vitro and in vivo probes of 5-HTR structure and function.

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Section: Introductionmentioning

confidence: 99%

Novel Bivalent 5-HT_2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

Soto

Shashack

Fox

et al. 2017

ACS Chem. Neurosci.

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“…Over the past few decades the understanding of GPCR structure and function has been challenged by the discovery that GPCRs are able to form homo- and hetero-oligomeric complexes. − The existence of homo- and heterodimers has been demonstrated for several class A GPCRs including opioid receptors, − adrenergic receptors, somatostatin receptors, , dopaminergic receptors, − muscarinergic receptors, , and the histamine receptor subtypes. ,− The term bivalent ligand is widely used and refers to molecules containing two sets of pharmacophoric entities linked through a spacer. − It is assumed that duplication of the pharmacophoric groups according to the bivalent ligand approach leads to a supra-additive increase in potency compared to the corresponding monovalent ligand.. , This concept has been studied for various GPCRs, for instance, for opioid receptors or aminergic GPCRs such as serotonin or dopamine receptor subtypes, − in more detail. The bivalent ligand approach in the design of ligands targeting GPCRs has proven to be promising to improve not only potency and selectivity but also the pharmacokinetic profile of compounds …”

Section: Introductionmentioning

confidence: 99%

The Bivalent Ligand Approach Leads to Highly Potent and Selective Acylguanidine-Type Histamine H₂ Receptor Agonists

et al. 2012

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Bivalent histamine H(2) receptor (H(2)R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by N(G)-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H(2)R agonism in GTPase and [(35)S]GTPγS binding assays at guinea pig (gp) and human (h) H(2)R-Gsα(S) fusion proteins including various H(2)R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H(1), H(3), and H(4) receptors. The bivalent ligands are H(2)R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH(2)R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H(2)R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH(2) groups) to simultaneously occupy two orthosteric binding sites in H(2)R dimers are nearly inactive, whereas the highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H(2)R dimers. The high agonistic potency may result from interaction with an accessory binding site at the same receptor protomer.

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“…In this study, we show that chemotactic repellents can be made into attractants when multivalent repellent ligands cluster their target receptors. For some GPCRs, treatment with antibodies or multivalent ligands – can elicit an agonist response. In addition, disparate signaling outcomes with monovalent and multivalent ligands have been observed in epidermal growth factor signaling .…”

Section: Resultsmentioning

confidence: 99%

Chemical Probes of Bacterial Signal Transduction Reveal That Repellents Stabilize and Attractants Destabilize the Chemoreceptor Array

2008

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The signal transduction cascade responsible for bacterial chemotaxis serves as a model for understanding how cells perceive and respond to their environments. Bacteria react to chemotactic signals by migrating toward attractants and away from repellents. Recent data suggest that the amplification of attractant stimuli depends on receptor collaboration: occupied and unoccupied chemoreceptors act together to relay attractant signals. Attractant signal transmission, therefore, depends on the organization of the chemoreceptors into a lattice of signaling proteins. The importance of this lattice for transducing repellent signals was unexplored. Here, we investigate the role of inter-receptor communication on repellent responses in Escherichia coli. Previously, we found that multivalent displays of attractants are more potent than their monovalent counterparts. To examine the importance of the chemoreceptor lattice in repellent signaling, we synthesized ligands displaying multiple copies of the repellent leucine. Monomeric leucine and low-valency leucine-displaying polymers were sensed as repellents. In contrast, multivalent displays of leucine capable of binding multiple chemoreceptors function not as potent repellents but as attractants. Intriguingly, chemical cross-linking studies indicate that these multivalent ligands, like monovalent attractants, disrupt the cellular chemoreceptor lattice. Thus, repellents stabilize the intrinsic chemoreceptor lattice, and attractants destabilize it. These results indicate that signals can be transmitted with high sensitivity via the disruption of protein-protein interactions. Moreover, our data demonstrate that repellents can be transformed into attractants merely by their multivalent display. These results have implications for designing agonists and antagonists for other signaling systems.

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Agonistic and Antagonistic Bivalent Ligands for Serotonin and Dopamine Receptors Including their Transporters

Cited by 21 publications

References 37 publications

Novel Bivalent 5-HT_2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

Novel Bivalent 5-HT_2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

The Bivalent Ligand Approach Leads to Highly Potent and Selective Acylguanidine-Type Histamine H₂ Receptor Agonists

Chemical Probes of Bacterial Signal Transduction Reveal That Repellents Stabilize and Attractants Destabilize the Chemoreceptor Array

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Agonistic and Antagonistic Bivalent Ligands for Serotonin and Dopamine Receptors Including their Transporters

Cited by 21 publications

References 37 publications

Novel Bivalent 5-HT2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

Novel Bivalent 5-HT2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

The Bivalent Ligand Approach Leads to Highly Potent and Selective Acylguanidine-Type Histamine H2 Receptor Agonists

Chemical Probes of Bacterial Signal Transduction Reveal That Repellents Stabilize and Attractants Destabilize the Chemoreceptor Array

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Product

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Novel Bivalent 5-HT_2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

Novel Bivalent 5-HT_2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo

The Bivalent Ligand Approach Leads to Highly Potent and Selective Acylguanidine-Type Histamine H₂ Receptor Agonists