Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.

A series of trans-1-piperazino-3-phenylindans were synthesized with the goal of replacing their established neuroleptic profile with that of peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds with an unsubstituted or fluoro-substituted 6-position in the indan ring, and which had a five- or six-membered heterocyclic ring attached by an ethylene chain to the piperazine ring, satisfied this objective. Some of the compounds had potent antihypertensive activity in conscious, spontaneously hypertensive rats (SHR). In pithed rats they antagonized the pressor effect induced by 5-HT in doses 100-1000 times lower than doses needed to antagonize the pressor effect of phenylephrine. The effect was stereoselective and associated with enantiomers with 1R,3S absolute configuration. 1S,3R enantiomers inhibited the uptake of dopamine and norepinephrine in vitro. The compound with the best antihypertensive activity was (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological profile resembled that of the standard compound ketanserin. There was a close structural correspondence between ketanserin and irindalone in a conformation that we recently identified as a D-2 receptor-relevant configuration of its neuroleptic "parent" tefludazine. This suggests that the dopaminergic (D-2) and the serotonergic (5-HT2) pharmacophores are structurally closely related.

Comparison of the effect of irindalone, a novel serotonin 5-HT2 antagonist and ketanserin on mechanical responses of rat thoracic aorta.

The relaxant effect of irindalone [+)-(1R, 3.S)-1-[2-[4-[3-(p-fluorophenyl)-1-indanyl]-1-piperazinyl] ethyl]2-imidazolidinone) and ketanserin was studies on active tension in isolated rat thoracic aorta. Irindalone and ketanserin caused a concentration-related inhibition of serotonin-induced contractions and shifted the serotonin curve to the right. Irindalone was more potent in inhibiting the serotonin-induced contractions and ketanserin was. The slopes of the Schild plots for the two substances were slightly, but not significantly, different from each other. This indicates that irindalone had a more pronounced serotonin antagonistic effect than ketanserin.

Comparative animal studies on cardiovascular toxicity of tri- and tetracyclic antidepressants and citalopram; relation to drug plasma levels.

The aim of the present study was to compare cardiovascular and/or cardiotoxic effects of eight anti-depressants (imipramine, chlorimipramine, amitriptyline, nortriptyline , doxepin, maprotiline, mianserin and citalopram) in anaesthetized cats after oral dosing and in conscious rabbits after intravenous infusion. In the cats drug plasma levels were determined as well. When estimated from ECG recordings, citalopram and chlorimipramine in particular, but also mianserin, appeared less cardiotoxic than the other drugs tested. The cardiovascular effects seen in the cats were with few exceptions identical for all the drugs tested but not seen at the same dose (concentration). Safety margins were defined as minimal doses or plasma levels when ECG changes (conduction or rhythm) or cardiovascular effects (+/- 10% change of initial value in a series of parameters) occurred in experimental animals divided by maximal therapeutic dose or mean plasma levels in patients. From comparisons of the safety margins it is concluded that except for citalopram and mianserin (safety margins 80 and 18 respectively in cats and greater than 15 in rabbits) all the other drugs tested (safety margins less than or equal to 9) have a cardiotoxic potential. The probability that cardiovascular side effects may occur is less pronounced for citalopram (safety margins 10-32) than for all the other drugs tested (safety margins ranging from 0.1 to less than 5).

Studies on acute toxicity and drug levels of citalopram in the dog.

Electrocardiographic and haemodynamic changes have been studied in conscious dogs after a sublethal oral dose (20 mg . kg-1) of citalopram. Furthermore, the effects of continuous intravenous infusion of citalopram (10 mg . kg-1 per hour) have been studied in conscious and anesthetized dogs. The findings have been related to plasma levels of citalopram. Severe convulsive attacks occurred in conscious dogs after infusion of 21.3 or 26.5 mg . kg-1 and after the oral dose. The convulsions were successfully treated with diazepam. In contrast convulsions were not seen in the anesthetized dogs. They died from respiratory arrest after infusion of 42.2 or 61.3 mg . kg-1. Atrioventricular and intraventricular conduction was unchanged and electrocardiographic changes were negligible. Sinus tachycardia which could be reversed by diazepam and moderate haemodynamic changes were seen. Since no electrocardiographic changes were seen in conscious dogs even during pauses in the convulsive seizure it is concluded that citalopram does not exert cardiotoxic effects in the dog. Good correlation was found between general clinical findings and citalopram levels in plasma. Conscious dogs were exposed to drug levels exceeding those of the average patient by a factor of about 20, while anesthetized dogs had considerable higher concentrations.

Effect of vasoactive intestinal polypeptide on cerebral blood flow in the goat.

The effect of vasoactive intestinal polypeptide (VIP) on the cerebral blood flow was investigated in the goat. An electromagnetic flow probe was placed around the internal maxillary artery for continuous measurement of ipsilateral blood flow. Intraarterial injection of VIP resulted in a dose-dependent increase in the cerebral blood flow. The effect was not antagonized by any of the antagonists atropine, propranolol, phentolamine and naloxone administered intraarterially 1 min before VIP. It is discussed that VIP may play a physiological role in the local blood flow regulation in the CNS.

Electrocardiographic and cardiovascular changes in cats and dogs caused by high doses of amitriptyline given as conventional tablets or a sustained release preparation.

Electrocardiographic and haemodynamic changes have been compared in anesthetized cats and in conscious dogs after high doses of amitriptyline given as conventional tablets or as a sustained release form. Plasma or serum levels of amitriptyline and nortriptyline were determined. In anaesthetized cats tablets caused marked ECG changes in all 6 animals combined with pronounced acidosis in 3 of the animals. The sustained release form caused no electrocardiographic changes in 4 animals and moderate disturbances in 2 animals, without acidosis in any of the 6 cats. Almost identical haemodynamic changes were seen in both groups. The plasma levels did not indicate poorer absorption from one preparation than from the other. In conscious dogs tablets caused marked clinical signs including restlessness, sedation and convulsions (2 dogs). Pronounced electrocardiographic changes were seen in all 4 dogs. Bundle branch block developed in 3 dogs. The sustained release preparation caused slight to moderate sedation and no convulsions. Pronounced electrocardiographic changes without bundle branch block were seen in one dog. Moderate changes were seen in the remaining dogs. Acidosis was most pronounced after the tablets. The serum drug levels clearly show that the absorption is much slower after administration of the sustained release preparation than after tablet administration and that somewhat lower amounts of drug are absorbed from the sustained release preparation than from tablets. It is evident from the present studies, that administration of high doses of amitryptyline as a sustained release preparation causes less toxic manifestations than given as conventional tablets. Part of the explanation may be that less amitryptyline is absorbed from the sustained release preparation than from tablets because of the high dose (dogs), but the main reason is most likely that the absorption from the sustained release preparation is much slower than the absorption from tablets.

Neuroleptic blockade of the effect of various neurotransmitter substances.

The antagonistic effect of neuroleptics to acetylcholine, histamine, 5-HT, and noradrenaline was examined in various in vivo and in vitro models. Piflutixol, a new potent thioxanthene neuroleptic, markedly antagonizes the effect of dopamine, noradrenaline, 5-HT and to some extent histamine, whereas the affinity for muscarinic receptors was rather weak. Clozapine and chlorprothixene on the other hand, have high affinity for muscarinic receptors and also antagonize the effect of histamine and 5-HT, whereas clozapine was a weak antagonist of noradrenaline and dopamine when compared to the effect of piflutixol. Chlorprothixene, however, also exhibits a rather good antagonism of noradrenaline and dopamine. Haloperidol proved to be weak in all models when compared with the other neuroleptics examined. Flupenthixol specifically antagonizes dopamine and noradrenaline, whereas fluphenazine was a more potent antagonist of dopamine than of the other transmitters. The data show, that neuroleptic compounds possess very different profiles with regard to interaction with various neurotransmitter substances. It is suggested, that the rather potent anti 5-HT and antihistamine effects observed for certain substances may contribute to the central effect of these drugs.

The pharmacology of a new potent, long acting neuroleptic, piflutixol.

Piflutixol, 6-fluoro-9-[3-(4-(2-hydroxyethyl)piperidino)propylidene]-2-trifluoromethyl-thioxanthene, has been shown to have pronounced neuroleptic properties. It is a very potent inhibitor of methylphenidate-induced stereotypies in mice, amphetamine and apomorphine-induced stereotypies in rats, apomorphine-induced stereotypies and vomiting in dogs. Furthermore piflutixol causes cataleptic reaction in small doses and inhibits conditioned avoidance reaction in rats. The compound is equally potent orally and parenterally and has a prolonged effect. Piflutixol has up to the present proved to be the most potent inhibitor of dopamine-stimulated adenylate cyclase in rat striatum in vitro. Piflutixol has a stron sedative effect (inhibition of spontaneous motor activity, induction of ptosis and potentiation of barbiturate anaesthesia) and in addition inhibits reticular arousal reaction in very low doses. Thus piflutixol constitutes a unique combination of potent anti-stereotyped activity with potent sedative effects. This means that piflutixol may prove to be a low-dose basic neuroleptic with long duration of action.

Pharmacology of cis(Z)-clopenthixol decanoate, a depot neuroleptic.

The duration and intensity of the neuroleptic effect of cis(Z)-clopenthixol decanoate in Viscoleo have been compared with those of cis(Z)-clopenthixol, 2 HCl in aqueous solution in a number of animal experimental models. Cis(Z)-clopenthixol, 2 HCl had a strong, but short-lasting neuroleptic effect (apomorphine antagonistic effect in dogs, inhibition of conditioned avoidance response in rats) which was accompanied by marked sedation. In contrast, cis(Z)-clopenthixol decanoate in oil had an effect which was slower in onset, but of much longer duration and only the highest doses caused a slight sedation. In rats catalepsy could be induced in some animals by high doses of cis(Z)-clopenthixol decanoate whereas cis(Z)-clopenthixol, 2 HCl at all the doses tested caused catalepsy in all animals. In mice only high doses of cis(Z)-clopenthixol decanoate in oil caused reduction of spontaneous motor activity and potentiation of barbiturate anaesthesia. The results are discussed with special reference to the clinical use of the depot preparation.