期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 12, 页码 3105-3114出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.04.026
关键词
D-4 ligand; D-4 selective ligand; Aryl piperazine; Phenyl piperazine; Benzothiazole; Benzofuran; Benzoxazole
资金
- NIH [5SC1GM088451-01-04]
- Title III Grant
- RCMI [5 G12MD007582-30]
- Pharmaceutical Research Center NIH/NCRR Grant [1C06-RR12512-01]
The dopamine D-4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D-4 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 DAD(4) 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 D-4 receptor. Compound 27 (KiD4 = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D-4 receptor. Compound 28 (KiD4 = 3.9 nM) while not as potent, was more discriminatory for the D-4 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, 5HT(1A)R and 5HT(2B)R, have binding affinity constants better than 100 nM (K-i < 100 nM). Compound 28 is a potentially useful D-4-selective ligand for probing disease treatments involving the D-4 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. Published by Elsevier Ltd.
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