Involvement of 5-Hydroxytryptamine and Bradykinin in the Hyperalgesia Induced in Rats by Collagenase from Clostridium Histolyticum

in Naunyn-Schmiedeberg's Archives of Pharmacology (1997), 355(5), 566-70

The involvement of bradykinin, 5-hydroxytryptamine, substance P and prostanoids in the hyperalgesia elicited by collagenase in rat paw was investigated. Collagenase (100 micrograms) induced a slight ... [more ▼]

The involvement of bradykinin, 5-hydroxytryptamine, substance P and prostanoids in the hyperalgesia elicited by collagenase in rat paw was investigated. Collagenase (100 micrograms) induced a slight hyperalgesia in kininogen deficient rats in comparison with the behavioural response obtained in normal rats. Lisinopril (10(-5) M), and angiotensin-converting enzyme inhibitor, increased the duration of the hyperalgesia elicited in normal rats. Ondansetron (0.5 to 5 mumol/kg), a 5-HT3 antagonist, suppressed the hyperalgesia as did methysergide (1.1 to 11 mumol/kg), a mixed 5-HT1 and 5-HT2 receptor antagonist. However, the hyperalgesia was not modified by RP 67580 (1.8 to 18 mumol/kg), a NK1 receptor antagonist, and was only slightly delayed by indomethacin (2 mg/kg), a cyclo-oxygenase inhibitor. The oedema-promoting effect of 5-HT (6 nmol) was inhibited by methysergide but not by ondansetron. The swelling induced by collagenase in rat paw was reduced by methysergide but not by ondansetron. We conclude that the behavioural response induced by collagenase depends on an interactions between bradykinin and 5-HT. Prostanoids play a minor role in the beginning of the reaction whereas substance P is not significantly involved in this hyperalgesia. [less ▲]

Tentatives de synthèse énantiosélective des isomères R et S du pirlindole

Poster (1997, May)

Dopamine D4 selective ligands as potential antipsychotics

in Awouters, Frank (Ed.) Proceedings of the XIVth International Symposium on Medicinal Chemistry (1997)

Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties.

in Pharmacological Research (1997), 36(1), 23-33

Pirlindole is a tetracyclic compound that has been characterized as a potential antidepressant drug. It has pharmacological characteristics in common with both tricyclic antidepressants and classical ... [more ▼]

Pirlindole is a tetracyclic compound that has been characterized as a potential antidepressant drug. It has pharmacological characteristics in common with both tricyclic antidepressants and classical irreversible monoamine oxidase inhibitors. Its main mechanism of action consists of a selective and reversible inhibition of monoamine oxidase A. Secondarily, it exerts an inhibitory effect on noradrenaline and 5-hydroxytryptamine reuptakes. It has no effect on the dopaminergic and cholinergic systems. It has only a low potential for amplifying tyramine and noradrenaline pressor effect, which makes one expect that it will not be at the basis of a 'cheese effect'. Pirlindole has an absolute bioavailability of between 20 and 30% due to an extensive first-pass effect. Orally, the Tmax varies between 2.5 and 6 h in the rat and 0.8 and 2 h in the dog. Two phases of elimination (7.5 and 34-70 h) are measured in the rat and three phases in the dog (1.3, 10.8 and 185 h); it is extensively metabolized. The rat eliminates mainly unconjugated products while the dog eliminates mostly conjugated products. Acute and chronic toxicological studies have not revealed potentially dangerous effects of the drug at the usual doses. It does not present measurable mutagenic, clastogenic or carcinogenic properties. Thus, pirlindole shows pharmacological, pharmacokinetic and toxicological properties which make it suitable for the management of depression. [less ▲]

Ligand effects in the hydrogenation of methacycline to doxycycline and epi-doxycycline catalysed by rhodium complexes. Molecular structure of the key catalyst [closo-3,3-(η2,3-C7H7CH2)-3,1,2-Rh C2B9H11]

in Journal of Organometallic Chemistry (1997), 536-537

Influence of Several Peptidase Inhibitors on the Pro-Inflammatory Effects of Substance P, Capsaicin and Collagenase

in Naunyn-Schmiedeberg's Archives of Pharmacology (1996), 354(5), 662-9

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability ... [more ▼]

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators. [less ▲]

Dibenzoazepine analogues : the electrophysiological properties of JL3, a potential atypical antidepressant

in European Journal of Pharmacology (1996), 310

Synthesis and diuretic properties of pyrid-3-ylsulfonylcyanoguanidines

Poster (1995, June)

Peroxidase-Catalysed Oxidation of Different Dibenzazepine Derivatives

in Archiv der Pharmazie (1995), 328(2), 109-12

According to a recent hypothesis suggesting the potential role of free radical formation in the clozapine-induced agranulocytosis, we have evaluated the susceptibility to the peroxidase-mediated oxidation ... [more ▼]

According to a recent hypothesis suggesting the potential role of free radical formation in the clozapine-induced agranulocytosis, we have evaluated the susceptibility to the peroxidase-mediated oxidation of different dibenzazepine analogues. On the one hand, compounds with an arylamine group such as clozapine or isoclozapine present a high reactivity in the horseradish peroxidase or myeloperoxidase systems and, on the other hand, fluperlapine, though known to induce agranulocytosis, and other dibenzothiazepine and dibenzoxazepine derivatives appear insensitive to oxidation. Consequently, among tricyclic derivatives, the way of diaryloxa- and diarylthiazepine compounds could be an alternative for the development of safer drugs such as antipsychotics. [less ▲]

11-(4-methylpiperazin-1-yl)-5H-pyrido[4,3-b][1,5]benzodiazepine

in Acta Crystallographica Section C-Crystal Structure Communications (1995), C51