trans-2,6-, 3,6- and 4,6-Diaza-5,6,6a,7,8,12b-hexahydrobenzo[C]phenanthrene-10,11-diols as dopamine agonists

Gu, Yu; Bayburt, Erol K.; Michaelides, Michel; Lin, Chun Wei; Shiosaki, Kazumi

doi:10.1016/s0960-894x(99)00214-0

Cited by 10 publications

(7 citation statements)

References 14 publications

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“…Interestingly, the 2-aza analogue (20 c) is a nonselective partial agonist with 10-fold lower affinity than 20 a. [75] Additional structurally similar DHX analogues included in the dataset were the inactive compounds Ro 21-7767 (24), [51] cis-DHX (25) [51] and (À)-DHX (26), [76] which show affinity for neither the D 1 nor D 2 receptors. [30,49] To the best of our knowledge, there are no known full D 1 agonists which do not comprise a catechol moiety, but there are several known partial agonists.…”

Section: Dataset Of Dopamine D 1 Ligandsmentioning

confidence: 99%

Selective Pharmacophore Models of Dopamine D₁ and D₂ Full Agonists Based on Extended Pharmacophore Features

et al. 2010

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This study is focused on the identification of structural features that determine the selectivity of dopamine receptor agonists toward D(1) and D(2) receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor (the Ser residues in TM5 and the Asp in TM3), a directional aromatic feature in the ligand, a feature with large positional tolerance representing the positively charged nitrogen in the ligand, and sets of excluded volumes reflecting the shapes of the receptors. The sets of D(1) and D(2) ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. The robustness of the models in discriminating actives from inactives was tested against four ensembles of conformations generated by using different established methods and different force fields. The reasons for the selectivity can be attributed to both geometrical differences in the arrangement of the features, e.g., different tilt angels of the pi system, as well as shape differences covered by the different sets of excluded volumes. This work provides useful information for the design of new D(1) and D(2) agonists and also for comparative homology modeling of D(1) and D(2) receptors. The approach is general and could therefore be applied to other ligand-protein interactions for which no experimental protein structure is available.

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Section: Dataset Of Dopamine D 1 Ligandsmentioning

confidence: 99%

Selective Pharmacophore Models of Dopamine D₁ and D₂ Full Agonists Based on Extended Pharmacophore Features

et al. 2010

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“…In the present study we developed dopamine D 1 receptor models to better understand the molecular basis for selectivity between full agonists and structurally similar inactive compounds. We focused on characterizing the binding site for agonists using available published binding selectivity data25–28 and mutation data 29. 30 Dopamine D 1 receptor structure models with all loops except the third intracellular loop (IC3) were built by using the structure of the human β 2 adrenergic receptor (adrb2; PDB code: 2RH1) as template.…”

Section: Introductionmentioning

confidence: 99%

Investigation of D₁ Receptor–Agonist Interactions and D₁/D₂ Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling

et al. 2012

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The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.

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“…Other attempts aimed at replacing the thiophene moiety by pyridine yielded several series of novel analogs. The best from these attempts were quite comparable to the best in the thiophene series in terms of receptor affinity, receptor selectivity D 1 /D 2 and intrinsic activity [138].…”

Section: Responses Of Central Neurons To Piribedil and 2-bromo-α-mentioning

confidence: 83%

Dopamine Agonists in the Treatment of Parkinsons Disease-Past, Present and Future

Sit

2000

CPD

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An attempt is made by the author to highlight the important events that laid the foundation of dopamine agonists as a treatment strategy for Parkinson s disease. This debilitating neurodegenerative disorder is long recognized as a result of progressive cell loss in the substantia nigra of the midbrain. The destruction of dopaminergic neurons with projections to the striatum results in the diminishing striatal dopamine levels. Anticholinergic drugs were once widely used to counteract the relative overactivity of cholinergic output from the basal ganglia and the strategy was only met with limited success. The discovery of dopamine depletion and the use of levodopa - a dopamine metabolic precursor, led the way to dopamine replacement therapy . The initial success with levodopa was soon overshadowed by the long-term side effects associated with levodopa. Many new drugs were developed with the hope to replace or strengthen the usefulness of levodopa. Apomorphine and ergot alkaloids have been around for some time; they are recently joined by newer dopamine agonists such as ropinirole and pramipexole. Each of these has its own characteristics and has occupied a place in the pharmacotherapy of Parkinson s disease. In this review older aporphines and ergot alkaloids are discussed first. More emphasis is directed to the side-effect profiles, metabolism and pharmacokinetics in terms of their unique chemical structures. The most recent agonists will be briefly discussed before we move on to the future - the future of emerging novel classes of promising dopaminergic agonists.

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trans-2,6-, 3,6- and 4,6-Diaza-5,6,6a,7,8,12b-hexahydrobenzo[C]phenanthrene-10,11-diols as dopamine agonists

Cited by 10 publications

References 14 publications

Selective Pharmacophore Models of Dopamine D₁ and D₂ Full Agonists Based on Extended Pharmacophore Features

Selective Pharmacophore Models of Dopamine D₁ and D₂ Full Agonists Based on Extended Pharmacophore Features

Investigation of D₁ Receptor–Agonist Interactions and D₁/D₂ Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling

Dopamine Agonists in the Treatment of Parkinsons Disease-Past, Present and Future

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trans-2,6-, 3,6- and 4,6-Diaza-5,6,6a,7,8,12b-hexahydrobenzo[C]phenanthrene-10,11-diols as dopamine agonists

Cited by 10 publications

References 14 publications

Selective Pharmacophore Models of Dopamine D1 and D2 Full Agonists Based on Extended Pharmacophore Features

Selective Pharmacophore Models of Dopamine D1 and D2 Full Agonists Based on Extended Pharmacophore Features

Investigation of D1 Receptor–Agonist Interactions and D1/D2 Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling

Dopamine Agonists in the Treatment of Parkinsons Disease-Past, Present and Future

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Selective Pharmacophore Models of Dopamine D₁ and D₂ Full Agonists Based on Extended Pharmacophore Features

Selective Pharmacophore Models of Dopamine D₁ and D₂ Full Agonists Based on Extended Pharmacophore Features

Investigation of D₁ Receptor–Agonist Interactions and D₁/D₂ Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling