112960-12-0Relevant academic research and scientific papers
Synthesis and Pharmacology of trans-4-n-Propyl-3,4,4a,10b-tetrahydro-2H,5H-1-benzopyrano-1,4-oxazin-7- and -9-ols: THe Significance of Nitrogen pKa Values for Central Dopamine Receptor Activation
Dijkstra, Durk,Mulder, Theo B. A.,Rollema, Hans,Tepper, Pieter G.,Weide, Jan Van der,Horn, Alan S.
, p. 2178 - 2182 (1988)
The 6-oxa analogues of potent dopamine agonists, hexahydronaphthoxazines (4a, 4b), have been tested for dopamine receptor binding and stimulating activity and were found to be almost inactive. pKa value determinations indicated that these compounds are protonated to ca. 2percent, while potent compounds are protonated to a much greater extent.These results strongly support the assumption that the protonated form of DA agonists is the active species at the receptor.
Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D3R Bitopic Agonists
Battiti, Francisco O.,Newman, Amy Hauck,Bonifazi, Alessandro
, p. 1956 - 1964 (2020/03/13)
In this study, starting from our selective D3R agonist FOB02-04A (5), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the trans-cyclopropyl moiety into a trans-cyclohexyl scaffold. Moreover, to further elucidate the importance of the primary pharmacophore stereochemistry in the design of bitopic ligands, we investigated the chiral requirements of (+)-PD128907 ((+)-(4aR,10bR)-2)) by synthesizing and resolving bitopic analogues in all the cis and trans combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2H,5H-chromeno[4,3-b][1,4] oxazine scaffold. Despite the lack of success in obtaining new analogues with improved biological profiles, in comparison to our current leads, a "negative"result due to a poor or simply not improved biological profile is fundamental toward better understanding chemical space and optimal stereochemistry for target recognition. Herein, we identified essential structural information to understand the differences between orthosteric and bitopic ligand-receptor binding interactions, discriminate D3R active and inactive states, and assist multitarget receptor recognition. Exploring stereochemical complexity and developing extended D3R SAR from this new library complements previously described SAR and inspires future structural and computational biology investigation. Moreover, the expansion of chemical space characterization for D3R agonism may be utilized in machine learning and artificial intelligence (AI)-based drug design, in the future.
Synthesis and Dopamine Agonist Properties of (+/-)-trans-3,4,4a,10b-Tetrahydro-4-propyl-2H,5H-benzopyrano-1,4-oxazin-9-ol and Its Enantiomers
DeWald, Horace A.,Heffner, Thomas G.,Jaen, Juan C.,Lustgarten, David M.,McPhail, Andrew T.,et al.
, p. 445 - 450 (2007/10/02)
The dopamine agonist profile of (+/-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-benzopyrano-1,4-oxazin-9-ol (16a) and its enantiomers (16b-c) was examined.Racemic 16a exhibited moderate affinity for the dopamine (DA) D2 receptor labe
