New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans

Journal of Medicinal Chemistry
R E MewshawT H Andree

Abstract

A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studie...Continue Reading

References

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Citations

Jan 30, 2002·Bioorganic & Medicinal Chemistry Letters·Richard E MewshawTerrance H Andree
Jan 8, 2014·European Journal of Medicinal Chemistry·Cecilia MattssonClas Sonesson
Jul 15, 2015·European Journal of Medicinal Chemistry·Carlo MateraClelia Dallanoce
Jan 13, 2000·Bioorganic & Medicinal Chemistry·G B McGaughey, R E Mewshaw
Sep 4, 2017·Journal of Molecular Modeling·Oscar ParraviciniRicardo D Enriz
Feb 27, 2018·Journal of Huntington's Disease·Susanna WatersNicholas Waters
Dec 17, 2008·Journal of Medicinal Chemistry·Magid Abou-Gharbia
Dec 6, 2014·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Vladimir ShalgunovPhilip H Elsinga
Oct 24, 2006·European Journal of Pharmacology·Julia N HeinrichTerrance H Andree

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