Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library was written by Maennel, Barbara;Jaiteh, Mariama;Zeifman, Alexey;Randakova, Alena;Moeller, Dorothee;Huebner, Harald;Gmeiner, Peter;Carlsson, Jens. And the article was included in ACS Chemical Biology in 2017.COA of Formula: C4H9Cl2N3 This article mentions the following:
Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Mol. docking of known functionally selective ligands to a D2R homol. model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chem. moieties via a linker was docked to the D2R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and 尾-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound I stimulated 尾-arrestin recruitment (EC50 = 320 nM, Emax = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed. In the experiment, the researchers used many compounds, for example, (1H-Imidazol-2-yl)methanamine dihydrochloride (cas: 22600-77-7COA of Formula: C4H9Cl2N3).
(1H-Imidazol-2-yl)methanamine dihydrochloride (cas: 22600-77-7) belongs to imidazole derivatives. The solubility of imidazoles in ethers is lower than that in alcohols and decreases with increasing chain length of the ethers . In contrast, the solubility of benzimidazoles in alcohols (C3鈥揅6) is higher than in water and generally decreases with a Imidazole is incorporated into many important biological compounds. The most pervasive is the amino acid histidine, which has an imidazole side-chain. Histidine is present in many proteins and enzymes, e.g. by binding metal cofactors, as seen in hemoglobin.COA of Formula: C4H9Cl2N3
Referemce:
Imidazole – Wikipedia,
Imidazole | C3H4N2 – PubChem