Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SAR

Medicinal Chemistry, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 03/2007; 17(3):745-9. DOI: 10.1016/j.bmcl.2006.10.076
Source: PubMed

ABSTRACT A series of analogues of the dopamine D2 receptor antagonist L741,626 were synthesized and evaluated for binding and function at D2 family receptor subtypes. Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity.

  • [Show abstract] [Hide abstract]
    ABSTRACT: On the basis of pharmacological behaviour dopamine receptors are divided into D1 and D2 subtype. These are primarily responsible for several neurophysiological anomalies. Assessment and validation with SPECT based conjugates provides a promising and cost effective insight to detect molecular changes in such neurological diseases. Spiperone, a well known “butryophenone” based D2 receptor antagonist has been explored to design a novel conjugate for SPECT evaluation. The molecular docking pose analysis of design molecule was explored with dopamine D2 receptor. The molecule was showing high affinity (-51.318 kcal/mol) due to conserved interactions with Asp114 and Phe389 of D2 receptor. DTPA with triazaspirodecanone moiety of spiperone was synthesized using bifunctional chelation approach with 88% yield and has been characterized using NMR and mass spectroscopy. The radiolabeling efficiency of 99mTc-DTPA-bis-(1-phenyl1,3,8-triazaspiro[4,5]decan-4-one) was 98%. The complex showed appreciable brain uptake in mice. The receptor binding experiments revealed a Kd of 6.26 nM with maximum localization of the conjugate in the striatum. Thus, these studies could be viewed as a novel and informative, initial proof-of-concept approach to the field of 99mTc-labeled radioligand design.
    RSC Advances 09/2014; 4(91). DOI:10.1039/C4RA07004F · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Flavones have antioxidant, anti-proliferative, anti-tumor, anti-microbial, estrogenic, acetyl cholinesterase, anti-inflammatory activities and are also used in cancer, cardiovascular disease, neurodegenerative disorders etc. Due to the wide range of biological activities of flavones have generated interest among medicinal chemists. This review may provide an opportunity to scientists of medicinal chemistry discipline to design selective, optimize as well as poly-functional flavone derivatives for the treatment of multi-factorial diseases.
    ChemInform 09/2014; 84:206–239. DOI:10.1016/j.ejmech.2014.07.013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Different parts of Podocarpus henkelii have been used in many cultures around the world to treat ailments such as cholera, stomach diseases, rheumatism, cancer, canine distemper in dogs and gall sickness in cattle. The aim of this study was to evaluate the biological activity and toxicity of isolated compounds from Podocarpus henkelii after an earlier study indicated a promising activity in crude extracts against viral pathogens of veterinary importance. Methods The antibacterial and antifungal activity of two biflavonoids 7, 4’, 7”, 4”’-tetramethoxy amentoflavone (TMA), isoginkgetin (IGG) and podocarpus flavone–A (PFA) isolated from the leaves of Podocarpus henkelii were determined using a serial microplate dilution method with tetrazolium violet as growth indicator. The cytotoxicity of compounds TMA and IGG were determined on different cell types using a tetrazolium-based colorimetric cellular assay (MTT). The Ames test was used to determine their mutagenic activities. Results TMA had reasonable antifungal activity against Aspergillus fumigatus (MIC = 30 μg/ml). IGG had a wide spectrum of activity against four bacterial and two fungal pathogens with much higher selectivity index values obtained for A. fumigatus and Cryptococcus neoformans (SI > 30). PFA had a broad spectrum of activity against Enterococcus faecalis and Pseudomonas aeruginosa (SI > 15) and less activity against the two fungal pathogens. In both the cytotoxicity assays and Ames mutagenicity test using Salmonella typhimurium strains TA98 and TA100, TMA and IGG had no deleterious effect on the different cell types and did not induce mutations in the Ames test. Conclusion Although the antimicrobial activities of the isolated compounds were not that exciting, the compounds had no cytotoxic activity at the highest concentration (1000 μg/ml) tested against all three cell lines. IGG was the most active against E. coli, S. aureus, A. fumigatus and C. neoformans, exhibiting both antibacterial and antifungal activity with good selectivity index values. PFA had a broad spectrum of activity against E. faecalis and P. aeruginosa. The two compounds isolated had low toxicity and no genotoxic activity in the Ames test.
    BMC Complementary and Alternative Medicine 10/2014; 14(1):383. DOI:10.1186/1472-6882-14-383 · 1.88 Impact Factor

Full-text (3 Sources)

Available from
Jun 1, 2014