1610591-72-4

Upstream product

• 24424-99-5 di-tert-butyl dicarbonate 
• 39512-49-7 4-(4-chlorophenyl)-4-hydroxypiperidine 
• 39684-80-5 2-(tert-butoxycarbonylamino)ethyl bromide 

Downstream Products

• 1610591-86-0 3-amino-N-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)ethyl)-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide 

Relevant academic research and scientific papers

Potent haloperidol derivatives covalently binding to the dopamine D2 receptor

The dopamine D2 receptor (D2R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D2R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D2R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments.

Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor

Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.