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Identification of C10 nitrogen-containing aporphines with dopamine D₁ versus D₅ receptor selectivity.

ABSTRACT: New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT_1A and 5-HT_2A receptors and at human dopamine D₁, D₂ and D₅ receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D₅ receptor, thus attaining D₁ versus D₅ selectivity. Compound 20c was the most potent D₁ ligand identified. Docking studies at D₁ and D₅ receptors indicate that the binding mode of 20c at the D₁ receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D₅ receptor, accounting for its D₁ versus D₅ selectivity. Considering the lack of affinity for the D₅ receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D₁ receptor tools.

SUBMITTER: Karki A

PROVIDER: S-EPMC7067653 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Identification of C10 nitrogen-containing aporphines with dopamine D1 versus D5 receptor selectivity.

Karki Anupam A Juarez Reecan R Namballa Hari K HK Alberts Ian I Harding Wayne W WW

Bioorganic & medicinal chemistry letters 20200220 8

New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT1A and 5-HT2A receptors and at human dopamine D1, D2 and D5 receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from ...[more]

PMID: 32107165

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Project description:Functional selectivity (or biased agonism) is a property exhibited by some G protein-coupled receptor (GPCR) ligands, which results in the modulation of a subset of a receptor's signaling capabilities and more precise control over complex biological processes. The dopamine D2 receptor (D2R) exhibits pleiotropic responses to the biogenic amine dopamine (DA) to mediate complex central nervous system functions through activation of G proteins and β-arrestins. D2R is a prominent therapeutic target for psychological and neurological disorders in which DA biology is dysregulated and targeting D2R with functionally selective drugs could provide a means by which pharmacotherapies could be developed. However, factors that determine GPCR functional selectivity in vivo may be multiple with receptors, ligands and transducers contributing to the process. We have recently described a mutagenesis approach to engineer biased D2R mutants in which G protein-dependent ([Gprot]D2R) and β-arrestin-dependent signaling ([βarr]D2R) were successfully separated (Peterson, et al. PNAS, 2015). Here, permutations of these mutants were used to identify critical determinants of the D2R signaling complex that impart signaling bias in response to the natural or synthetic ligands. Critical residues identified in generating [Gprot]D2R and [βarr]D2R conferred control of partial agonism at G protein and/or β-arrestin activity. Another set of mutations that result in G protein bias was identified that demonstrated that full agonists can impart unique activation patterns, and provided further credence to the concept of ligand texture. Finally, the contributions and interplay between different transducers indicated that G proteins are not aberrantly activated, and that receptor kinase and β-arrestin activities are inextricably linked. These data provide a thorough elucidation of the feasibility and malleability of D2R functional selectivity and point to means by which novel in vivo therapies could be modeled.

Project description:BackgroundG protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins plays an important role in the cellular regulation of responses to external stimuli. Despite intensive structural research, the mechanism underlying the receptor-G protein coupling of closely related subtypes of Gαi remains unclear. In addition to the structural changes of interacting proteins, the interactions between lipids and proteins seem to be crucial in GPCR-dependent cell signaling due to their functional organization in specific membrane domains. In previous works, we found that Gαs and Gαi3 subunits prefer distinct types of membrane-anchor lipid domains that also modulate the G protein trimer localization. In the present study, we investigated the functional selectivity of dopamine D2 long receptor isoform (D2R) toward the Gαi1, Gαi2, and Gαi3 subunits, and analyzed whether the organization of Gαi heterotrimers at the plasma membrane affects the signal transduction.MethodsWe characterized the lateral diffusion and the receptor-G protein spatial distribution in living cells using two assays: fluorescence recovery after photobleaching microscopy and fluorescence resonance energy transfer detected by fluorescence-lifetime imaging microscopy. Depending on distribution of data differences between Gα subunits were investigated using parametric approach-unpaired T-test or nonparametric-Mann-Whitney U test.ResultsDespite the similarities between the examined subunits, the experiments conducted in the study revealed a significantly faster lateral diffusion of the Gαi2 subunit and the singular distribution of the Gαi1 subunit in the plasma membrane. The cell membrane partitioning of distinct Gαi heterotrimers with dopamine receptor correlated very well with the efficiency of D2R-mediated inhibition the formation of cAMP.ConclusionsThis study showed that even closely related subunits of Gαi differ in their membrane-trafficking properties that impact on their signaling. The interactions between lipids and proteins seem to be crucial in GPCR-dependent cell signaling due to their functional organization in specific membrane domains, and should therefore be taken into account as one of the selectivity determinants of G protein coupling. Video abstract.

Dataset Information

Identification of C10 nitrogen-containing aporphines with dopamine D₁ versus D₅ receptor selectivity.

Publications

Identification of C10 nitrogen-containing aporphines with dopamine D<sub>1</sub> versus D<sub>5</sub> receptor selectivity.

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