Synthesis, X-ray Crystallography, and Pharmacokinetics of Novel Azomethine Prodrugs of (R)-.alpha.-Methylhistamine: Highly Potent and Selective Histamine H3 Receptor Agonists

Krause, Michael; Rouleau, A.; Stark, Holger; Luger, Peter; Lipp, Ralph; Garbarg, M.; Schwartz, Jean‐Charles; Schunack, Walter

doi:10.1021/jm00020a022

Cited by 47 publications

(18 citation statements)

References 13 publications

(27 reference statements)

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“…, is a prodrug of (R)-α-methylhistamine, and 10 mg of it contains 4.1 mg of (R)-α-methylhistamine (Krause et al 1995;Rouleau et al 1997). Scopolamine hydrobromide was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice

Onodera

Miyazaki

Imaizumi

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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Effects of FUB 181 [3-(4-chlorophenyl)propyl-3-(1H-imidazol-4-yl)propyl ether], a novel histamine H3-receptor antagonist, on a scopolamine-induced learning deficit in the elevated plus-maze test were studied in mice. FUB 181 alone (2.5 and 5 mg/kg, i.p.) ameliorated the scopolamine-induced learning deficit in mice. This effect was antagonized by BP 2.94 (10 mg/kg, i.p.), a prodrug of (R)-alpha-methylhistamine (histamine H3-receptor agonist), and by ketotifen (4 mg/kg, i.p.), a histamine H1-receptor antagonist, both penetrating the blood-brain barrier. However, the ameliorating effect of FUB 181 (2.5 mg/kg) was not antagonized by either terfenadine (10 mg/kg, i.p.), a histamine H1-receptor antagonist with poor penetration of the blood-brain barrier, or zolantidine (20 mg/kg, i.p.), a centrally effective histamine H2-receptor antagonist. In a biochemical study, FUB 181 had no significant effect on either acetylcholine or choline level in mice brain at the doses tested. These findings suggest that FUB 181 increases the release of histamine by blocking presynaptic histamine H3 autoreceptors, and that released histamine in turn activates postsynaptic H1 and H2 receptors, predominantly histamine H1 receptors, and in this fashion improves learning and memory in mice. Our findings also suggest that the histaminergic system may play an important role in learning and memory, and that FUB 181 may be a clinical candidate for the therapy of dementia.

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Section: Methodsmentioning

confidence: 99%

Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice

Onodera

Miyazaki

Imaizumi

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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“…This poor pharmacokinetic profile has tentatively been attributed to extensive methylation [158]. In an effort to improve this compound's pharmacokinetic properties, a prodrug approach was subsequently attempted [159]. The prodrug, BP 2.94, did have oral bioavailability and effectively released R--methylhistamine from the prodrug moiety in mice and humans, but neither the prodrug nor the active metabolite was detected in mouse brains after oral dosing [158].…”

Section: H 3 Agonists As Sleep-promoting Agentsmentioning

confidence: 99%

The Prevalence, Morbidities, and Treatments of Insomnia

Zammit

2007

CNSNDDT

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Insomnia is a common condition that often is co-morbid with other illnesses. It is associated with significant morbidities, including nighttime distress, impaired cognitive functioning, impaired daytime functioning, and increased risk of accidents. People with insomnia utilize healthcare services more often than those without insomnia, and they are at greater risk for the development of certain health problems; most notably psychiatric illness such as depression. It is now known that the significant impact of insomnia warrants diagnosis and treatment. Behavioral and psychopharmacological treatments have been available for some time. However, formerly common classes of therapeutics such as the barbiturates and benzodiazepines have been replaced by new allosteric modulators of the GABA(A) receptor and other therapeutics with novel mechanisms of action. This article presents existing approaches to insomnia treatment, and reviews new treatments, therapeutic targets, and treatment approaches to insomnia under development that may offer promise to practitioners and patients.

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“…For example, the fluorination of cloxacillin caused an increase in the free fraction of the drug in blood [4]. In addition, the fluorination of azomethine derivatives, histamine H 3 receptor antagonists, markedly enhanced the delivery of these drugs into the central nervous system, compared with azomethine derivatives [5].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of 9α-fluoromedroxyprogesterone acetate in rats: comparison with medroxyprogesterone acetate

Kozutsumi

Kawashima

Sugimoto

et al. 1999

Biopharm. Drug Dispos.

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Medroxyprogesterone acetate (MPA) is widely used in endocrine therapy for breast cancer and other diseases. Recently, it has been demonstrated that 9α‐fluoromedroxyprogesterone acetate (FMPA) also has anti‐tumour activity in chemical‐induced rat mammary tumour and its activity is greater than that of MPA. In the present study, the physico‐chemical properties of FMPA and MPA and their pharmacokinetics in female rats were investigated. Partition coefficients (log P) of FMPA and MPA were 3.1 and 3.8, respectively, while the solubilities of FMPA and MPA in phosphate buffer saline were 3.8 and 1.1 μg/mL, respectively. When the two agents were intravenously or orally administered into female rats, there was no significant difference between their plasma concentrations. However, unmetabolized drug excreted into urine accounted for 4.7 and 0.7% of the intravenous dose of FMPA and MPA, respectively. The free fraction of FMPA in rat plasma was approximately four times that of MPA. Assuming the well‐stirred model, hepatic intrinsic clearances of FMPA and MPA were estimated to be 64 and 293 L/h per kg, respectively. In addition, the free fraction of FMPA in blood is estimated to be higher than that of MPA, which may explain the higher anti‐tumour activity. Copyright © 1999 John Wiley & Sons, Ltd.

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Synthesis, X-ray Crystallography, and Pharmacokinetics of Novel Azomethine Prodrugs of (R)-.alpha.-Methylhistamine: Highly Potent and Selective Histamine H3 Receptor Agonists

Cited by 47 publications

References 13 publications

Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice

Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice

The Prevalence, Morbidities, and Treatments of Insomnia

Pharmacokinetics of 9α-fluoromedroxyprogesterone acetate in rats: comparison with medroxyprogesterone acetate

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