Abstract
In this study, we evaluated the activities of new types of azaphenothiazines in the following immunological assays: the proliferative response of human peripheral blood mononuclear cells induced by phytohemagglutin A or anti-CD3 antibodies; lipopolysaccharide-induced cytokine production by human PBMC; the secondary, humoral immune response in mice to sheep erythrocytes (in vitro); and delayed-type hypersensitivity in mice to ovalbumin (in vivo). In some tests, chlorpromazine served as a reference drug. The compounds exhibited differential inhibitory activities in the proliferation tests, with 10H-2,7-diazaphenothiazine (compound 1) and 6-(3-dimethylaminopropyl)diquinothiazine (compound 8) being most suppressive. Compound 1 was selected for further studies, and was found to be strongly suppressive in the humoral immune response even at low concentrations (1 μg/ml). Compound 1 also inhibited the delayed-type hypersensitivity lipopolysaccharide-induced production of tumor necrosis factor and interleukin-6 in cultures of human blood cells. As there were only two subjects in this study, the effects of these compounds on human blood cells need to be confirmed. In this paper, we also discuss the structure-activity relationships of selected compounds.
Key words: Azaphenothiazines, Immune response, PBMC, Proliferation, Cytokines
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Abbreviations used
- AFC
antibody-forming cells
- CNS
central nervous system
- DMF
dimethylformamide
- DMSO
dimethyl sulfoxide
- DTH
delayed-type hypersensitivity
- FCS
fetal calf serum
- GI50
inhibition of cell growth (the concentration needed to reduce the growth of treated cells to half that of untreated cells)
- IFN-γ
interferon gamma
- IL
interleukin
- i.p.
intraperitoneally
- LPS
lipopolysaccharide
- MDR
multidrug resistance
- MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- NS
not significant
- OVA
ovalbumin
- PBMC
peripheral blood mononuclear cells
- PHA
phytohemagglutinin
- RPMI-1640
Rosewell Park Memorial Institute Medium
- s.c.
subcutenaously
- SRBC
heep red blood cells
- TNF-α
tumor necrosis factor alpha
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