C.J. de Vos

Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, org 3770 and its enantiomers

The neurochemical and autonomic pharmacological profile of 1,2,3,4,10, 14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c]pyrido[2, 3-c] [2] benzazepine [+/-)Org 3770) and the related antidepressant drug, mianserin, have been compared. The uptake of [3H]noradrenaline ([3H]NA) in vitro was weakly affected by (+/-)Org 3770 (pKi = 5.6) in contrast to mianserin (pKi = 7.4). Both (+/-)Org 3770 and mianserin facilitated the release of [3H]NA in slices of cortex. The effects of NA mediated by alpha 2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKi values of 8.4 and 8.1, respectively. However, (-)Org 3770 only antagonized the effect of NA on the release of [3H]5-HT (pA2 = 7.7). The binding of [3H]rauwolscine to alpha 2-adrenoceptors was inhibited by (+/-)Org 3770 and mianserin with identical affinity (pKi = 7.0), whereas the binding of [3H]prazosin to alpha 1-adrenoceptors was less potently affected by (+/-)Org 3770 (pKi = 6.4) than by mianserin (pKi = 7.1). A similar difference was found for alpha 1- and alpha 2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2 receptors was less potently blocked by (+/-)Org 3770 (pKi = 8.1) than by mianserin (pKi = 9.4) while the binding of [3H]mepyramine to histamine-1 receptors was more potently affected by (+/-)Org 3770 (pKi = 9.3) than by mianserin (pKi = 8.75). The binding of [3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (+/-)Org 3770 (pKi = 6.1) and mianserin (pKi = 6.3). Similar data on tryptamine-D, histamine-1 and muscarinic cholinergic receptors in isolated organs were obtained. A prominent role for the blockade of alpha 2-adrenoceptors in the therapeutic effects of mianserin and (+/-)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA.

Mianserin hydrochloride: Peripheral and central effects in relation to antagonism against 5-hydroxytryptamine and tryptamine

Abstract Mianserin hydrochloride, a new anti-5-hydroxytryptamine agent, was compared with cyproheptadine with respect to a variety of responses evoked by 5-hydroxytryptamine and other agonists. Central effects against tryptamine responses and general depressant effect on CNS were also studied. The two antagonists induced comparable inhibition against responses in which D-receptors of 5-HT were involved. Mianserin displayed α-adrenolytic activity and did not antagonize muscarinic effects of acetylcholine; the opposite was true for cyproheptadine. Mianserin was more effective than cyproheptadine in counteracting tryptamine-induced responses in rabbits and rats. Cyproheptadine produced diffuse depression of the CNS, with marked elevation of the threshold to electric stimulation of the brain stem reticular system in rabbits, persistent block of the acoustic arousal in rats and rabbits and prolongation of barbiturate sleep in rats. Mianserin however did not produce CNS depression, other than transient inhibition of the sensory activation of the EEG in rabbits. The earlier postulated structure-activity relationship between mianserin and cyproheptadine does not appear to apply to effects other than certain 5-HT responses and central tryptamine effects.

1-Hydroxy-3-amino-pyrrolidone-2 (HA-966): A new GABA-like compound, with potential use in extrapyramidal diseases

1 The drug HA‐966 (1‐hydroxy‐3‐amino‐pyrrolidone‐2), which chemically resembles the cyclic form of GABA, has been studied for neuro‐pharmacological properties and for effects on the catecholamine content of the corpus striatum. 2 The acute effects on spontaneous behaviour of rodents included flaccid catalepsy and reversible tranquillization in doses which were 5% or less of the lethal dose. Long lasting depression of the CNS, followed by complete recovery, was produced in the cat and the dog. In the monkey HA‐966 caused periodical sleeping episodes. 3 The exploratory behaviour and the amphetamine‐induced motor activity in mice were blocked by HA‐966. The toxicity of amphetamine in aggregated mice was only moderately reduced, suggesting that HA‐966 differs from neuroleptics. 4 Tremors induced by chemical agents (nicotine, zinc and tremorine) were markedly inhibited by HA‐966. The muscarinic effects of tremorine were not reduced by HA‐966, indicating a selective central antitremor effect. 5 HA‐966 elevated the threshold to strychnine convulsions and abolished the ipsilateral flexor reflex, while not having motor endplate blocking properties. It is suggested that HA‐966 depresses central internuncial neurones. 6 In rats and rabbits HA‐966 produced synchronous EEG and inhibited the sensory arousal in doses not causing sedation. In the monkey the drug caused a periodical dissociation between ‘sleep‐EEG’ and behaviour. 7 In rat brain, HA‐966 selectively elevated the dopamine content in the corpus striatum, while no changes in noradrenaline and 5‐hydroxytryptamine contents could be demonstrated. The effect was still present when dopa synthesis was inhibited with α‐methyl‐p‐tyrosine. 8 Several effects of intravenously administered HA‐966 became manifest after an appreciable delay and in hepatectomized mice the effects were much reduced. It is postulated that HA‐966 is converted to a pharmacologically active metabolite. 9 The results are discussed in the light of current views on drug therapy in extrapyramidal conditions and a GABA‐related hypothesis as to the mode of action of HA‐966 is presented.

Haemorrhagic mechanisms of some snake venoms in relation to protection by estriol succinate of blood vessel damage

Abstract The vascular haemorrhagic action of cobra venom depends on the presence of a heparin precipitable material, the latter being possibly the so called Direct Lytic Factor, which apparently renders the phospholipase of the venom capable of causing bleeding. The haemorrhagic action of Agkistrodon piscivorus venom is independent of a heparin precipitable factor and it is also unlikely that the phospholipase activity of the venom is responsible for the haemorrhages. Estriol succinate counteracts the bleedings caused by cobra venom, but not the haemorrhages produced by the snake venom lacking the heparin precipitable factor.

Method for study of snake venom induced hemorrhages.

Abstract A method to study the vascular hemorrhagic effects of snake venoms is described. It consists of topical application of the venoms to the lung surface in dog open-chest preparations and allows qualitative and quantitative assessment of the hemorrhages. The venoms of Naja naja and Naja nigricollis produced diffuse bleedings, while hemorrhages caused by the venom of Agkistrodon piscivorus had a petechial character. A. piscivorus venom displayed two to three times the potency of N. naja venom with regard to onset and intensity of the hemorrhages. Both venoms contain heparin precipitable materials. Addition of heparin to the Naja venoms abolished their hemorrhagic activity, while the A. piscivorus venom retained the hemorrhagic effect. A possible relationship between the hemorrhagic effects and some enzymatic activities of the venoms is discussed. There was no correlation between hemorrhagic and BAEE-esterasic activity of the venoms. It is unlikely that phospholipase-A alone plays a role in the hemorrhagic effect.

Specific oedema-inhibiting property of a natural anti-inflammatory factor collected from inflamed tissue

Eine hochmolekulare Verbindung wurde aus Exudaten von Granulombeuteln von Ratten gereinigt. Diese Substanz, i.p. an Ratten verabreicht, hemmt das durch Kaolin oder durch Carrageenin erzeugte Pfotenoedem, nicht dagegen das durch Histamin, Serotonin oder Polyvinylpyrrolidon erzeugte Oedem.

Significance of the kinin system in rat paw oedemas and drug effects on it

Abstract Total kininogen plus kinin activity was estimated in fluids collected from different types of rat paw oedema and also under conditions of pretreatment with either cyproheptadine or phenylbutazone. Elevated activity was found when serotonin or kaolin were used as subplantar irritants, but not when polyvinylpyrrolidone served as the oedema inducer. Rat paw oedema is thus not necessarily associated with the kinin system. Cyproheptadine reduced the total kinin activity and paw swelling induced by serotonin but not by kaolin. Phenylbutazone reduced both parameters with kaolin as the oedema producer, but failed to have any effect with serotonin as irritant. Although the two drugs are known to antagonize some effects of kinin, in this study they interfered, each in a different way, with production of either kininogen or kinin.

Presence of a slow-contraction inducing material in fluid collected from the rat paw oedema induced by serotonin

Ein biologisch aktives Prinzip in der Ödemflüssigkeit aus Rattenpfoten nach Serotoninbehandlung ist wahrscheinlich nicht Serotonin oder Acetylcholin, sondern zum geringeren Teil eine histaminähnliche, zum grösseren Teil jedoch eine Substanz, die ähnliche Eigenschaften wie Bradykinin zeigt.

Dissociation of Oedema Provoking Factor of Agkistrodon Piscivorus Venom from Kininogenase

The development of a method for measuring the hemorrhagic activity qualitatively as well as quantitatively by Bonta et al. (1) made it possible to characterise the hemorrhagic factors of some venoms. These factors were revealed to be basic polypeptides of less than 10,000 molecular weight. Since hemorrhages are known to accompany a variety of allergic inflammations and since it has also been found that oestriol succinate inhibits the hemorrhages (2) as well as the cobra venom induced rat paw oedema (3,9), it seemed worthwhile investigating whether some venom fractions which induce pulmonary hemorrhages are able to induce oedema. In addition some chemical and pharmacological properties of these fractions have been investigated.

The pharmacological profile of Org 6906, a potential non-sedative antidepressant that combines monoamine uptake inhibition with alpha2-adrenolytic activity

(dl)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-8-amine hydrochloride (Org 6906) is a potential new antidepressant agent, with a neurochemical profile quite different from that of the classical tricyclic antidepressant drugs. The compound was found active in behavioural tests which are considered to be predictive for antidepressant activity, such as the muricidal test in the rat and the acquired immobility model. Neurochemical studies showed that Org 6906 was an inhibitor of the reuptake of monoamines both in vitro and ex-vivo without having appreciable anticholinergic, antihistaminergic or alpha 1-adrenolytic activity. The facilitatory effect on monoaminergic neurotransmission was confirmed by the reversal of hypothermia induced by reserpine. The drug Org 6906 appeared to have selective alpha 2-adrenolytic properties. It facilitated potassium-stimulated release of noradrenaline from slices of cortex, displaced [3H]rauwolscine and [3H]dihydroergocryptine from their binding sites but only weakly blocked alpha 1-adrenoceptors. The alpha 2-adrenolytic properties were also apparent in behavioural interaction models. The compound antagonized the sleep-inducing effects of clonidine in chicks and mice and it antagonized the mydriasis induced by clonidine in the rat. Finally, it was shown that the two enantiomers of Org 6906 contributed almost equally to the relevant neurochemical and behavioural properties.