129281-28-3Relevant academic research and scientific papers
Identification of a new selective dopamine D4 receptor ligand
Sampson, Dinithia,Zhu, Xue Y.,Eyunni, Suresh V.K.,Etukala, Jagan R.,Ofori, Edward,Bricker, Barbara,Lamango, Nazarius S.,Setola, Vincent,Roth, Bryan L.,Ablordeppey, Seth Y.
, p. 3105 - 3114 (2014/06/09)
The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (K iD4 = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4 = 3.9 nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100 nM (Ki 4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.
Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents
Peprah, Kwakye,Zhu, Xue Y.,Eyunni, Suresh V.K.,Setola, Vincent,Roth, Bryan L.,Ablordeppey, Seth Y.
, p. 1291 - 1297 (2012/04/11)
Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that haloperidol can serve as a useful lead in the identification and design of new agents that target multiple receptors associated with antipsychotic pharmacology.
