Tricyclic epines. Novel (E)- and (Z)-11H-dibenz[b,e]azepines as potential central nervous system agents. Variation of the basic side chain.

The synthesis and pharmacological activity of new (E),(Z)-[6-(alkylamino)-11H-dibenz[b,e]azepin-11- ylidene]acetonitriles 12-45 and (E),(Z)-[6-(aminoalkoxy)-11H-dibenz[b,e]azepin-11-ylidene] acetonitriles 46-51 are described. The introduction of the cyanomethylene group into the 11-position of the 11H-dibenz[b,e]azepine framework has been carried out by a Wittig-Horner reaction under mild conditions. The (E),(Z) isomers were separated by fractional crystallization, assignment being achieved by X-ray analysis. A number of (E),(Z)-[6-(alkylamino)-11H-dibenz-[b,e]azepin-11-ylidene] acetonitriles (12, 14, 16, 20) show potent neuroleptic activity (2-7 times that of clozapine) in animal tests. The screening included tests for sedative and anticholinergic activity in mice, apomorphine and tryptamine antagonism in rats, and muscle-relaxing activity in rabbits. The divergence in the activity profile in the case of the separated (E),(Z) isomers has been observed as an interesting new aspect: the (Z) isomers show a significantly higher sedative and muscle-relaxant activity, whereas the (E) isomers possess a higher anticholinergic efficacy and somewhat greater apomorphine antagonism. Broad changes in the basic side chain were made in order to investigate structure-activity relationships. The important geometrical parameters for the molecules, obtained by X-ray analysis, were compared with the corresponding features in dopamine agonists and antagonists.

L-dopa potentiating analogs of Pro-Leu-Gly-NH2 with oral efficacy.

Chemical modification of PLG, comprising replacement of proline or/and leucine by unnatural amino acids led to analogs with high oral efficacy. The most active analog identified in the course of our works was 1-prolyl-2-phenyl-1-2-aminobutanoylglycinamide (Doreptide). Doreptide is presently further evaluated as a new drug for the treatment of Parkinson's disease.

[Central and peripheral interactions of the antiparkinson agent biperiden and the antihistaminic bamipin on the rat excited by pilocarpine]. / Zentrale und periphere Interaktionen des Antiparkinsonmittels Biperiden und des Antihistaminikums Bamipin bei der Erregung der Ratte durch Pilocarpin.

Excitatory reactions elicited by pilocarpine HCl (50 mg/kg i.v. in 6 s) are used for demonstrating synergistic effects of the central anticholinergic drug biperiden (Akineton) and the antihistamine bamipine (Soventol). Scratching movements of the hind legs are used as parameter for central activity, salivation for peripheral and death for toxic drug effect, respectively. The results show distinct synergistic (central) activity of drug combinations concerning the inhibition of scratching movements. On the contrary, no intensified inhibition is found with the peripheal symptom salivation bamipine rather induces an attenuation of inhibitory effects seen after hig doses of biperiden. Furthermore, the enhanced toxicity of pilocarpine caused by bamipine in a defined dosage range is antagonized by biperiden in a dose related manner. The results of the animal experiments presented are paralleled with clinical experience.

Stimulation of a specific drive (predatory behaviour) by p-chlorophenylalanine (pCPA) in the rat.

In contrast to wild rats the percentage of animals showing predatory behaviour is very low among laboratory rats. Stimulation of this specific drive by systemic drug application has been mentioned only for pCPA and delta9-tetrahydrocannabinole. As detailed investigations concerning this stimulating property of pCPA are not published, the effect was studied in selected non-biting rats (without starvation and isolation) regarding dose- and time-dependence after single and repeated drug administration; further, D- and L-isomers of pCPA were included in the investigation. After single oral application of 200 to 3200 mg/kg DL-pCPA a dose-dependent stimulation of predatory behaviour was found. Smaller doses (200 or 400 mg/kg p.o.) given repeatedly on 3 consecutive days showed effects comparable with those after single administration of much higher doses (1600 or 3200 mg/kg p.o.). With repeated oral application of 50, 100 or 200 mg/kg on 10 consecutive days no difference was found between D- and L-pCPA concerning efficacy and time course of drug effect. Both after single and repeated administration in all series of tests the effect reached its maximum not before several days and faded almost completely in the drug-free after-period. D-methamphetamine HCl, investigated comparatively as a CNS stimulant, provoked no predatory behaviour in a wide dose-range (0.125 to 8.0 mg/kg p.o.) with repeated administration on 10 consecutive days. Within the control groups (total number of rats = 100) no animal showed predatory attach during an observation-period of at least 3 weeks.

Pharmacology of amezinium, a novel antihypotensive drug. VI. Effect on central nervous functions.

4-Amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in this study briefly called amezinium, was tested for possible central effects taking particular account of the mechanisms of action found for this substance in other studies. 1. The most conspicuous action of amezinium was in modifying reserpine-induced ptosis and reserpine-induced hypothermia. When amezinium is given before reserpine, the ED50 values are 0.15 and 3.9 mg/kg p.o. for both mouse and rat. These effects can be explained by a peripheral site of action since peripheral sympathomimetic effects can also be demonstrated in this dose range. Higher doses (10 mg/kg and upwards p.o.) were required to abolish reserpine-induced hypothermia 17 h after reserpine administration, an effect which probably requires a central site of action. But for imipramine, desipramine and pargyline the effective doses are the same in both experimental models (administration before and after reserpine, respectively). 2. Amezinium potentiated the effect of a threshold dose of L-dopa. Based on the central symptoms, higher doses (10 mg/kg p.o.) were also required for this effect. 3. With blood pressure increasing doses, the sleeping-waking pattern was modified in that duration and number of REM-episodes were reduced; in cats there was no parallel increase of wakefulness whilst in rats there was a slight relative increase of wakefulness. 4. Amezinium, particularly at high doses (46.4 mg/kg and upwards), exhibited a central depressant effect on the spontaneous behaviour of mice and rats and on orientational hyperactivity of mice. Based on the modification of aggregation toxicity, the effect of methamphetamine was reduced. In no dose range was there any evidence of methamphetamine-like effects (increase of motor activity, inhibition of food intake and increase of aggregation toxicity). 5. Amezinium did not affect the duration of hexobarbital anaesthesia or the coordination of mice on a rotating rod. 6. The acute toxicity of amezinium in mice and rats was low. The oral LD50 for mice was 1630 mg/kg and for rats 1410 mg/kg.

Induction of hyperphagia in rats by intracerebroventricular infusion of sodium pentobarbital. A method for testing anorexigenic compounds.

In rats hyperphagia could be reversibly induced by intracerebroventricular infusion of sodium pentobarbital. Hyperphagia was elicited in a dose dependent manner, the optimal infusion rate being 1000 micrograms/h sodium pentobarbital. At this rate, feeding behaviour was induced selectively, with only minor side effects being apparent. Systemic application of d-methamphetamine or propylhexedrine given prior to infusion resulted in a dose dependent reduction of hyperphagia. The method, therefore, could be useful for testing putative anorexigenic compounds in hyperphagic rats.

[Pharmacological characterization of the new highly potent beta-adrenergic receptor blocker soquinolol]. / Pharmakologische Charakterisierung des neuen, hochwirksamen beta-Rezeptorenblockers Soquinolol.

The present pharmacological test results characterize soquinolol (5-[3-tertiary butylamino-2-hydroxypropoxy]-2-formyl-1,2,3,4- tetrahydroisoquinoline mucate, We 704, Sertum) as a highly potent non-subtype-selective beta-adrenergic receptor blocker, which is devoid of any intrinsic sympathomimetic activity. Its localanaesthetic activity (membrane stabilizing effect) is very weak. It also shows good enteral efficacy and long duration of action. In binding studies with heart (Ki beta 1 = 3.25 nmol/l) and lung membranes (Ki beta 2 = 0.85 nmol/l) its binding profile was found to be similar to that of propranolol. Soquinolol inhibits the isoprenaline-induced tachycardia (EC50% = 48 micrograms/l) in the guinea-pig Langendorff heart in vitro to the same degree as propranolol. However, in the conscious dog soquinolol's beta 1-adrenergic blocking activity (ED 50%) on intravenous injection (5.5 micrograms/kg) and oral administration (5.8 micrograms/kg) is about twice as great as that of pindolol and 19 times (i.v.) or 138 times (p.o.) greater than that of propranolol. These results suggest 95% enteral efficacy for soquinolol (pindolol 88%, propranolol 13%). The differences in soquinolol's and propranolol's efficacy detected in vitro and in vivo are partially attributable to differences in their kinetic properties namely the lower protein binding and the higher distribution volume of soquinolol. In the conscious dog, soquinolol inhibits beta 1-(ED 50% = 4.0 micrograms/kg) and beta 2-receptors (ED 50% = 2.7 micrograms/kg) at dose levels which do not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological studies on propafenone and its main metabolite 5-hydroxypropafenone.

The new antiarrhythmic drug propafenone and its main human metabolite 5-hydroxypropafenone were investigated for antiarrhythmic, local anaesthetic, Ca++-antagonistic and beta-adrenoceptor blocking effects as well as for their activity on the central nervous system. In isolated organs (guinea-pig atria, rat aortic strips) 5-hydroxypropafenone had a smaller effect on the maximum following frequency, a greater negative inotropic effect, a greater Ca++-antagonistic effect and a very distinctly weaker beta-adrenoceptor blocking effect than propafenone. Consistent with its antiarrhythmic potency in vitro, intra-cutaneous 5-hydroxypropafenone had a smaller local anaesthetic effect in the guinea pig wheal. In contrast to these findings 5-hydroxypropafenone showed a stronger antiarrhythmic potency in vivo (rat and dog), as demonstrated on the aconitine- and infarction arrhythmias. In addition, in His bundle studies 5-hydroxypropafenone caused a more marked prolongation of the conduction time in atria, AV-node and His-Purkinje system. In vivo the beta-adrenoceptor blocking effect of 5-hydroxypropafenone (isoprenaline tachycardia, rat) was smaller than that of propafenone. The difference between the in vitro and in vivo potency of 5-hydroxypropafenone may be explained by differences in pharmacokinetics, e.g. by a smaller distribution volume compared to propafenone. CNS effects were investigated due to local anaesthetic properties of the substances tested. As indicator of CNS activity anticonvulsant effects, detectably beneath convulsion-inducing doses, were determined in rats (max. electroshock seizures). The results show low CNS activity of propafenone which is even lower for the metabolite but which is distinctly higher for lidocaine and - related to the antiarrhythmic potency - for flecainide, too.(ABSTRACT TRUNCATED AT 250 WORDS)