Structure-activity relationship in N3-alkyl-xanthine derivatives.

Takagi, Kenzo; Hasegawa, Takaaki; Kuzuya, Takafumi; Ogawa, Kenji; Watanabe, Tomonori; Satake, Tatsuo; Miyamoto, Katsuhiko; Wakusawa, Shinya; Koshiura, Ryozo

doi:10.1254/jjp.46.373

Cited by 26 publications

(15 citation statements)

References 19 publications

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“…These findings usefully supplement the structureactivity relationship for the adenosine-antagonizing action of xanthines reported by Persson et al (1982). There are reports that alkylation of the 1-and 3-position increases tracheal relaxant potency and that, within limits, an increase in the size of the 3-alkyl analogues also increases bronchodilator potency (Parker et al, 1956;Persson et al 1985;Takagi et al, 1988). For tracheal smooth muscle, cyclic AMP PDE activity is of 2 types, i.e., low Km (high-affinity) and high Km (low-affinity).…”

Section: Discussionsupporting

confidence: 58%

Mechanism of xanthine‐induced relaxation of guinea‐pig isolated trachealis muscle

Ogawa

Takagi

Satake

1989

British J Pharmacology

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1Four 3-alkylxanthines (3-methylxanthine, 3-n-propylxanthine (enprofylline), 3-n-butylxanthine and 3-iso-butylxanthine) and four 1-methyl-3-alkylxanthines (1-methyl-3-methylxanthine (theophylline), 1-methyl-3-n-propylxanthine, 1-methyl-3-n-butylxanthine and 1-methyl-3-iso-butylxanthine (IBMX)), were compared in terms of cyclic AMP phosphodiesterase (PDE) inhibition and trachealis muscle relaxation. The relationship between xanthine structure and cyclic AMP PDE inhibition was also studied. 2 Xanthine induced relaxation of guinea-pig isolated trachealis muscle was measured against spontaneous tone.3 The four 1-methyl-3-alkylxanthines were each significantly more potent than the corresponding 3-alkylxanthines in relaxing the isolated trachealis muscle. The 1-methyl-3-alkylxanthines were similarly more potent than the corresponding 3-alkyl derivatives in inhibiting low Km cyclic AMP PDE. There was a strong positive correlation between low Km cyclic AMP PDE inhibition and the tracheal smooth muscle relaxation evoked by the xanthine derivatives. 4 Since methylation of the 1-position of each 3-alkylxanthine increased the potency of the derivative in inhibiting low Km cyclic AMP PDE and in relaxing trachealis muscle and since a strong positive correlation was observed between the relaxant EC50 and the Ki value of each xanthine derivative, it is suggested that low Km cyclic AMP PDE inhibition by xanthines plays an important role in their tracheal relaxant effect.

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Section: Discussionsupporting

confidence: 58%

Mechanism of xanthine‐induced relaxation of guinea‐pig isolated trachealis muscle

Ogawa

Takagi

Satake

1989

British J Pharmacology

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“…13 Inulin was purchased from Nacalai Tesque (Kyoto, Japan). 13 Inulin was purchased from Nacalai Tesque (Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

Dose-Dependent Pharmacokinetics of Enprofylline and Its Renal Handling in Rats

Nadai

Hasegawa

Muraoka

et al. 1991

Journal of Pharmaceutical Sciences

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“…In addition, other pharmacological activities of MPBX are weaker than those of other xanthine derivatives. [12][13][14][15][16][17][18] Therefore, the combination with MPBX may allow separation of the IDA-induced antitumor activity and the adverse reaction.…”

Section: Discussionmentioning

confidence: 99%

Effects of 1‐Methyl‐3‐propyl‐7‐butylxanthine (MPBX) on Idarubicin‐induced Antitumor Activity and Bone Marrow Suppression

Sadzuka

Egawa

Sugiyama

et al. 2000

Japanese Journal of Cancer Research

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The effects of 1-methyl-3-propyl-7-butylxanthine (MPBX), a xanthine derivative, on idarubicin (IDA)-induced antitumor activity against P388 leukemia cells (P388) and bone marrow suppression were examined. In P388 tumor-bearing mice, the combination of MPBX with IDA increased the antitumor activity of IDA. The IDA concentration in the tumors in the MPBX combination group increased by 2.0-fold compared to the level in the IDA-alone group. On the other hand, as regards IDA-induced bone marrow suppression, the combination of MPBX with IDA reduced the decrease in the bone marrow cell number by 30% compared to that in the IDA-alone group. In addition, the IDA concentration in the bone marrow cells was decreased by the combination of MPBX with IDA. An in vitro experiment showed that MPBX facilitated IDA influx and suppressed IDA efflux in P388 cells. In conclusion, the combination of MPBX with IDA increased the antitumor activity and decreased the bone marrow suppression. Therefore, we expect that the combination of MPBX with IDA will be useful for leukemia chemotherapy.Key words: 1-Methyl-3-propyl-7-butylxanthine -Idarubicin -Antitumor activity -Adverse reaction -Bone marrow suppression Chemotherapeutic agents play important roles in cancer therapy, but there are many problems, including side effects and the appearance of resistant cells. Studies of biochemical modulation to enhance the antitumor activity and suppress side effects by means of combination treatment with non-antitumor drugs are being carried out and could improve the efficacy of cancer chemotherapy.In our previous study, we confirmed that caffeine, a xanthine derivative, increases the antitumor activity induced by doxorubicin (DOX) against Ehrlich ascites carcinoma cells through suppression of DOX efflux.1-3) Furthermore, it was confirmed that this inhibitory effect on DOX efflux is correlated with the structure of xanthine derivatives.4) 1-Methyl-3-propyl-7-butylxanthine (MPBX, Fig. 1) significantly suppresses DOX efflux and increases antitumor activity induced by DOX. 5,6) On the other hand, idarubicin (IDA), a newly synthesized anthracycline used in the treatment of acute myeloblastic leukemia, 7-10) can cause suppression of bone marrow cells and death in clinical use. Because IDA-induced antitumor activity is exerted on leukemia cells in the bone marrow and blood, it is impossible to separate the antitumor activity and side effects, so the use of IDA is limited. Most biochemical modulators increase the antitumor activity with a concomitant increase in side toxicity. But we confirmed that MPBX decreases the cardiotoxicity induced by DOX in addition to enhancing the antitumor activity of DOX. 11)Thus, the combination of MPBX with IDA might allow the separation of antitumor activity and bone marrow suppression.In this study, we examined the effects of MPBX on the antitumor activity and bone marrow suppression induced by IDA. The results indicate that combination treatment with IDA and MPBX could be useful for the treatment of leukemia. MATERIALS AND ME...

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Structure-activity relationship in N3-alkyl-xanthine derivatives.

Cited by 26 publications

References 19 publications

Mechanism of xanthine‐induced relaxation of guinea‐pig isolated trachealis muscle

Mechanism of xanthine‐induced relaxation of guinea‐pig isolated trachealis muscle

Dose-Dependent Pharmacokinetics of Enprofylline and Its Renal Handling in Rats

Effects of 1‐Methyl‐3‐propyl‐7‐butylxanthine (MPBX) on Idarubicin‐induced Antitumor Activity and Bone Marrow Suppression

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