thiourea and nordimaprit

Human melanoma cells were treated in culture with the histamine (H2) agonist S-(3-(N-N-dimethylamino)propyl)isothiourea (dimaprit), a partial agonist, S-(2-(N,N-dimethylamino)ethyl)-isothiourea (nordimaprit), and two analogues of nordimaprit, S-(2-(N,N-diethylamino)ethyl)isothiourea (DENOR) and S-(2-(N,N-diisopropylamino)ethyl)isothiourea (DINOR), to investigate the effects on toxicity and tyrosinase activity. Cell survival studies showed highest toxicity in the constitutively pigmented human melanoma cell line MM418, DINOR being the most effective agent. Toxicity was not blocked by the H2 antagonist cimetidine. Dimaprit and its derivatives decreased tyrosinase activity in the amelanotic human melanoma cell line MM96E and inhibited expression of a melanosomal antigen. Loss of tyrosinase activity could be prevented by cimetidine and ranitidine, an H2 antagonist. Although the tyrosinase activity in MM418 cells was much more resistant to inhibition by these agents compared with that in MM96E cells, prolonged growth in the presence of non-toxic levels of DINOR caused a decrease in tyrosinase activity and subsequent depigmentation. Ultrastructural examination of the depigmented cells showed a decrease in the number of melanized melanosomes and the appearance of premelanosomes. These results indicate that bulky substituents on the tertiary amine group in nordimaprit significantly enhance potency for depigmentation and cell killing but only the former effect is mediated by the H2 receptor.

Topics: Cell Division; Cell Survival; Cimetidine; Dimaprit; Humans; Immunoblotting; Melanoma; Microscopy, Electron; Monophenol Monooxygenase; Pigmentation; Ranitidine; Receptors, Histamine H2; Thiourea; Tumor Cells, Cultured

In cultured human melanoma cells, histamine H1 (mepyramine) and H2 receptor antagonists (cimetidine, ranitidine, impromidine) increased tyrosinase activity, whereas H2 agonists (dimaprit, nordimaprit) decreased activity. Mixtures of agonist and antagonist either decreased or increased tyrosinase activity, depending on the relative concentrations of each drug. Nordimaprit, the most effective inhibitor, lowered tyrosinase activity significantly within 36 h and caused a slower loss of tyrosinase protein as judged by reactivity with two monoclonal antibodies. Prolonged treatment of a melanotic cell line with nordimaprit led to complete loss of pigment, with no loss of the 56-kDa melanosomal antigen 1C11. Cells remained amelanotic for 8 weeks after removal of the drug and, even after 26 weeks, melanin content and tyrosinase expression and activity had not fully recovered. Nordimaprit increased the rate of degradation of tyrosinase and of nordimaprit binding proteins. Whereas nordimprit did not directly inhibit tyrosinase, lysates of treated cells contained an inhibitory activity that partitioned approximately equally across a 10-kDa ultrafiltration membrane. Overall, these results showed that melanogenesis can be controlled via histamine receptors, the mechanism for the H2 agonist nordimaprit consisting of three components: induction of a tyrosinase inhibitor, increased degradation of tyrosinase, and long-term down-regulation of tyrosinase expression.

Topics: Dimaprit; Flow Cytometry; Gene Expression Regulation, Enzymologic; Histamine H2 Antagonists; Humans; Melanoma; Methionine; Monophenol Monooxygenase; Receptors, Histamine H2; Sulfur Radioisotopes; Thiourea; Tumor Cells, Cultured

The effects of administration into the brain ventricle of H2 receptor agonists (4-methylhistamine, 0.8 mumol/rat; dimaprit, 0.4-0.8 mumol/rat), H2 antagonists (cimetidine, 0.8 mumol/rat; ranitidine, 0.4-0.8 mumol/rat; famotidine, 0.03 mumol/rat) and of the dimaprit chemical analogue SK&F 91487 (0.4 mumol/rat) on unstimulated and histamine-stimulated prolactin secretion in normal male rats were studied. The H2 agonist 4-methylhistamine caused a significant increase in unstimulated blood PRL, whereas dimaprit, SK&F 91487, and the H2 antagonists tested did not change PRL levels. 4-Methylhistamine significantly enhanced the stimulatory effects of histamine on prolactin, whereas all the H2 antagonists inhibited histamine-induced prolactin release. The inhibition of histamine-induced prolactin secretion by the H2 agonist dimaprit is nonspecific, since its chemical analogue SK&F 91487, which has no H2 agonist activity, also inhibits it. These results indicate that stimulation of the H2 receptors in the central nervous system is facilitatory for PRL secretion, suggesting that the activation of H2 receptors may contribute to the PRL-releasing effects of histamine.

Topics: Animals; Brain; Cimetidine; Dimaprit; Famotidine; Histamine H2 Antagonists; Injections, Intraventricular; Male; Methylhistamines; Prolactin; Ranitidine; Rats; Rats, Inbred Strains; Receptors, Histamine H2; Thiazoles; Thiourea

Topical application of the H2-histamine receptor agonist, dimaprit (S-[4-N,N-dimethylaminopropyl]isothiourea), produced eosinophil chemotaxis into the anterior segment of rabbit eyes only when an H2-antagonist was co-administered. Nordimaprit (S-[4-N,N-dimethylaminoethyl]isothiourea), a structural homologue of dimaprit that lacked activity at histamine receptors, produced eosinophil chemotaxis whether or not an H2-antagonist was co-administered. Onset of eosinophil chemotaxis began after 2 or more days of treatment, and was accompanied by corneal edema, opacification, and ocular inflammation. There was no concurrent eosinophilia in the peripheral blood or in the conjunctiva. The response occurred in pigmented and albino rabbit eyes, and was facilitated by prior co-administration of proparacaine eye drops. Another dimaprit homologue without activity at histamine receptors, homodimaprit (S-[4-N,N-dimethylaminobutyl]isothiourea), did not produce eosinophil chemotaxis when applied topically, nor did the H2-agonists impromidine, histamine, or 4-methylhistamine, whether co-administered with an H2-antagonist or not. It was concluded that dimaprit and nordimaprit produced a selective eosinophil chemotaxis unrelated to H1- and H2-histamine receptor activity. However, the H2-agonist activity of dimaprit appeared to inhibit this response unless neutralized by an H2-antagonist. Topical application of dimaprit with an H2-antagonist or nordimaprit alone may allow large numbers of non-degranulated eosinophils, free of other cell types, to be harvested from the aqueous humor.

Topics: Animals; Chemotaxis, Leukocyte; Cimetidine; Dimaprit; Eosinophils; Eye Color; Intraocular Pressure; Propoxycaine; Rabbits; Receptors, Histamine H2; Thiourea; Uveitis, Anterior

Methylamine and chloroquine both 'lysosomotropic' agents (i.e. agents which sequester in lysosomes) caused a dose-related inhibition of mitogen-induced lymphocyte activation in the concentrations which have previously been shown to increase the pH of lysosomes. The dose-response curves of inhibition of mitogen-induced lymphocyte activation for chloroquine and methylamine are very steep and are similar to the dose-response curves obtained with dimaprit and nordimaprit, but very different from the flat dose-response curves previously described for histamine. Approximate IC50 values were methylamine 6.4 mM, dimaprit 0.13 mM, nordimaprit 0.03 mM and chloroquine 18 microM. It is suggested that the mechanism of action of methylamine and chloroquine may be related to their lysosomotropic action and consequent interference with ligand-receptor processing, and that dimaprit and nordimaprit but not histamine may act by a similar mechanism.

Topics: Cells, Cultured; Chloroquine; Chromium Radioisotopes; Concanavalin A; Dimaprit; Histamine; Humans; Lymphocyte Activation; Lymphocytes; Methylamines; Mitogens; Phytohemagglutinins; Thiourea; Thymidine

Topics: Adult; Dermatitis, Contact; Dermatitis, Occupational; Dimaprit; Humans; Isothiuronium; Male; Patch Tests; Thiourea

Topics: Dermatitis, Contact; Dermatitis, Occupational; Dimaprit; Humans; Isothiuronium; Male; Middle Aged; Thiourea

Topics: Animals; Dermatitis, Contact; Dermatitis, Occupational; Dimaprit; Guinea Pigs; Humans; Isothiuronium; Patch Tests; Photography; Thiourea