ChemInform Abstract: Convenient and Efficient Synthesis of Some Novel Fused Thieno Pyrimidines Using Gewald′s Reaction.

Nirogi, Ramakrishna; Kambhampati, Rama Sastri; Kothmirkar, Prabhakar; Arepalli, Sobhanadri; Pamuleti, Narasimha Reddy G.; Shide, Anil K.; Dubey, P. K.

doi:10.1002/chin.201211147

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“…Docking of compound 1 in the D2R Raclo complex consistently yielded the best scoring pose shown in Figure 7. This pose is stabilised by a hydrogen bond between the ionised morpholine secondary amine and the oxygen atom of the side-chain of S409 7.36 (Ballesteros-Wenstein nomenclature 33 ), as well π-π stacking interactions of the thienopyrimidine moiety with Y408 7.35 and W100 ECL1 side chains. In addition, the fused cyclohexane ring system is positioned in the hydrophobic sub-pocket located between helices V and VI formed by the residues I184ECL2, V190 5.39 , H394 6.55 , whereas the phenyl ring bearing the m-CF3 substituent is placed between helices VI and VII, and ECL3, and is lined by the residues N396 6.58 , N402 ECL3 , P405 7.32 , and Y408 7.35 ( Figure 7).…”

Section: Radioligand Binding Analysis Of Analogues Ofmentioning

confidence: 99%

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor

et al. 2018

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Recently, a novel negative allosteric modulator (NAM) of the D-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3- d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.

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Section: Radioligand Binding Analysis Of Analogues Ofmentioning

confidence: 99%

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor

et al. 2018

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ChemInform Abstract: Convenient and Efficient Synthesis of Some Novel Fused Thieno Pyrimidines Using Gewald′s Reaction.

Cited by 1 publication

References 1 publication

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor

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ChemInform Abstract: Convenient and Efficient Synthesis of Some Novel Fused Thieno Pyrimidines Using Gewald′s Reaction.

Cited by 1 publication

References 1 publication

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor

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A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor