119075-35-3Relevant academic research and scientific papers
Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization
Kuhne, Sebastiaan,Kooistra, Albert J.,Bosma, Reggie,Bortolato, Andrea,Wijtmans, Maikel,Vischer, Henry F.,Mason, Jonathan S.,De Graaf, Chris,De Esch, Iwan J.P.,Leurs, Rob
, p. 9047 - 9061 (2016/10/22)
Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivatives to investigate the roles of (i) the amine-binding region, (ii) the upper and lower aromatic region, and (iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water molecule from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of 1. Deconstruction of 1 showed that the lower aromatic region serves as a secondary binding hot spot. This study demonstrates that an X-ray structure in combination with tool compounds, assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.
Dopamine/serotonin receptor ligands. 9.1 oxygen-containing midsized heterocyclic ring systems and nonrigidized analogues. A step toward dopamine D5 receptor selectivity
Wittig, Thomas W.,Decker, Michael,Lehmann, Jochen
, p. 4155 - 4158 (2007/10/03)
Eleven-membered heterocycles (dibenz[g,j]-1-oxa-4-azacycloundecenes) and open-chain analogues were synthesized and investigated for affinities to human dopamine receptor subtypes. The moderately rigidized rings displayed nanomolar and subnanomolar Ki values at D1-like receptors with a significant D1 to D2 and a slight D5 to D 1 selectivity. The open-chain analogues showed lower affinities but significant D1 to D2 selectivities. Compound 3 (K i(D5) = 0.57 nmol) showed antagonistic or inverse agonistic binding characteristics in a functional Ca assay.
