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.
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.
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