Oxatomide: The Prototype of a Chemical Series of Compounds Inhibiting Both the Release and the Effects of Allergic Mediators

Awouters, F.; Niemegeers, C. J. E.; Janßen, Paul; Janssen, M.; Vandenberk, J.; Kennis, Ludo; Aa, Marcel Van der; HEERTUM, A. VAN

doi:10.1021/bk-1980-0118.ch010

Cited by 4 publications

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“…antagonists, butyrophenones (spiperone, droperidol, bromperidol, haloperidol), the diphenylbutylpiperidine, pimozide, the 6,6,6-membered ring tricyclic, chlorpromazine [see reference in Leysen and Niemegeers, 19851, and the peripheral dopamine antagonist domperidone [Laduron and Leysen, 19791 were investigated. Amongst the histamine-H1 antagonists the new drugs investigated were astemizole [Laduron et al, 19821, oxatomide [Awouters et al, 1980), and levocabastine [Pipkorn et al, 19851; the reference compound was pyrilamine [see Laduron et al, 19821. Amongst the opiates, fentanyl derivatives (carfentanil, lofentanil, sufentanil, fentanyl, and alfentanil) [Leysen et al, 19831 were compared to morphine.…”

Section: Introductionmentioning

confidence: 99%

Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S₂, Dopamine‐D₂, histamine‐H₁ antagonists, and opiates

Leysen

Gommeren

1986

Drug Development Research

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Leysjen, J.E. and W. Gommeren: Drug-receptor dissociation time, new tool for drug research: Receptor binding affinity and drug-receptor dissociation profiles of serotonin-S2, dopamine-D2, histamine-H, antagonists, and opiates. Drug Dev. Res. 8:119-131, 1986.A new filter technique for in vitro measurement of the drug-receptor dissocation time of unlabeled compounds was applied. The receptor binding affinity and drug-receptor dissociation profiles were obtained for new and reference compounds belonging to the classes of serotonin-S2, dopamine-D2, and histamine-HI antagonists and of opiates. In vitro binding to the serotonin-S2, dopamine-D2, histamine-H, , adrenergic-a, and -a2, cholinergic muscarinic, and p-opiate receptors was studied. The binding affinity profiles provide indications about the specificity of the drugs; in each pharmacological class more selective drugs were found, whereas others cross-reacted with various receptor sites. The drug-receptor dissociation profiles revealed substantial differences amongst drugs in drug-receptor dissociation times. For a particular receptor, drugs showed differences in dissociation time from half-times of less than 1 min (e.g., alfentanil from opiate receptors) to several hours (e.g., lofentanil). In addition, drugs were found that dissociated very slowly from one receptor site and very rapidly from another receptor site (e.g., ritanserin: slow from serotonin-S2, rapid from dopamine-D2; spiperone: slow from dopamine-D2, rapid from serotonin-S2; astemizole: slow from histamine-HI, rapid from serotonin-S2 and adrenergica,). Nevertheless, apparent binding affinities of these drugs for the receptor sites respecReceived final version March 3, 1986; accepted March 3, 1986 Address reprint requests to Dr. J.E. Leysen, Department of Biochemistry Pharmacology, Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse, Belgium. 0 1986 Alan R. Liss, Inc. 120Leysen and Gommeren tively were often found to be similar. Information on the drug-receptor dissociation time allows re-evaluation of apparent binding affinity data and gives better insight into the specificity of action of drugs. It can be applied at various levels of drug research: e.g., for interpretation of receptor binding data, drug effects on receptor regulation, functional effects of drugs, antagonizability of drug effects, and factors contributing to the in vivo duration of action of drugs. Finally, the information on drug-receptor dissociation time may be an important factor for drug design and receptor modeling.

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Section: Introductionmentioning

confidence: 99%

Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S₂, Dopamine‐D₂, histamine‐H₁ antagonists, and opiates

Leysen

Gommeren

1986

Drug Development Research

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Further studies on the distinctive sleep‐wakefulness profiles of antihistamines (astemizole, ketotifen, terfenadine) in dogs

Wauquier

Broeck

Awouters

et al. 1984

Drug Development Research

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The effects of the antihistamines astemizole, ketotifen, and terfenadine, given orally at the dose of 10 mglkg, were investigated on 16-hr sleep-wakefulness patterns in dogs. As determined in the Ascaris allergy test in dogs, this dose had marked antihistaminic activity for at least the total duration of the recording. Using a computerized on-line analysis and automatic sleep classification, a differentiation was made between wakefulness, transition to sleep, slow-wave sleep, and REM (or paradoxical) sleep. Astemizole did not significantly change sleep-wakefulness patterns. Ketotifen significantly increased slow-wave sleep and significantly decreased REM sleep. Terfenadine significantly decreased wakefulness and significantly increased both slow-wave sleep and REM sleep. With both ketotifen and terfenadine, REM latency was prolonged. Two different mechanisms appear to be involved in the REM sleep effects seen with terfenadine: an early REM sleep suppressant effect and a late but large REM sleep-enhancing effect. This study shows central effects of terfenadine that are not completely typical for HI antagonists but which are very pronounced at a dose producing much weaker peripheral antihistamine activity than the same dose of ketotifen and astemizole. Key words: sleep-wakefulness patterns, dogs, antihistamines, astemizole, ketotifen, terfenadineHistamine is present in nonmast cells in brain, and is distinctly distributed in a way reminiscent of the distribution of catecholaminergic neurons [Schwartz, 19771. This feature along with the clinical observation that classical antihistamines or HI-receptor antagonists invariably produce sedation at antihistaminic dose levels suggests the involvement of histatninergic neurons in the mechanisms controlling wakefulness.

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Rocastine (AHR-11325), a rapid acting, nonsedating antihistamine

et al. 1989

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Rocastine [AHR-11325, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4- oxazepine-5(4H)-thione (E)-2-butenedioate)] is a rapid-acting, potent, nonsedating antihistamine. In guinea pigs challenged with a lethal dose of histamine, rocastine is as effective [based on 1 hr. oral, protective dose (PD50S)] as brompheniramine, chlorpheniramine, pyrilamine, and promethazine and superior to astemizole, diphenhydramine, terfenadine, and oxatomide. Rocastine has a faster onset of action than does terfenadine; rocastine being as effective with a 15 min pretreatment time (PD50 = 0.13 mg/kg) as it is with a 1 hr pretreatment time (PD50 = 0.12 mg/kg), while the 15 min PD50 of terfenadine (PD50 = 44.0 mg/kg) is 22 times greater than the 1 hr PD50 (PD50 = 1.93 mg/kg). Against aerosolized histamine, rocastine was 7.12 x, 2.63 x, and equipotent to pyrilamine in preventing histamine-induced prostration at pretreatment times of 1,3, and 6 hr, respectively. Rocastine protected guinea pigs from collapse induced by aerosolized antigen; rocastine was approximately 36 x more potent (based on 1 hr PD50) than diphenhydramine and as potent as oxatomide and terfenadine. Rocastine did not alter the EEG of cats at doses in vast excess (150x) of its antihistaminic dose nor did it potentiate yohimbine toxicity in mice. Further, rocastine possesses no anticholinergic, antiadrenergic, or antiserotonergic properties in vitro. Rocastine is a selective, nonsedating, H1-antagonist with a rapid onset of action.

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Oxatomide: The Prototype of a Chemical Series of Compounds Inhibiting Both the Release and the Effects of Allergic Mediators

Cited by 4 publications

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Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S₂, Dopamine‐D₂, histamine‐H₁ antagonists, and opiates

Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S₂, Dopamine‐D₂, histamine‐H₁ antagonists, and opiates

Further studies on the distinctive sleep‐wakefulness profiles of antihistamines (astemizole, ketotifen, terfenadine) in dogs

Rocastine (AHR-11325), a rapid acting, nonsedating antihistamine

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Oxatomide: The Prototype of a Chemical Series of Compounds Inhibiting Both the Release and the Effects of Allergic Mediators

Cited by 4 publications

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Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S2, Dopamine‐D2, histamine‐H1 antagonists, and opiates

Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S2, Dopamine‐D2, histamine‐H1 antagonists, and opiates

Further studies on the distinctive sleep‐wakefulness profiles of antihistamines (astemizole, ketotifen, terfenadine) in dogs

Rocastine (AHR-11325), a rapid acting, nonsedating antihistamine

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Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S₂, Dopamine‐D₂, histamine‐H₁ antagonists, and opiates

Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S₂, Dopamine‐D₂, histamine‐H₁ antagonists, and opiates