Pharmacological screening of a novel chromone-containing allylmorpholine using pharmacoencephalography in rats

Introduction. Chromone-containing allylmorpholines (CCAMs) represent a novel group of biologically active compounds with putative psychotropic activity. Pharmacoencephalographic screening of the molecule (E)-4-[3-(6-chloro-4-oxo-4H-chromen-3-yl)-4-cyclohexylallyl]morpholin-4-ium chloride (33a) demonstrated that its effects on EEG profiles are similar to those of the dopamine receptor antagonist sulpiride and the antihistamine hydroxyzine. The antipsychotic potential of this molecule has been further explored in behavioral tests in rats and mice. It can be hypothesized that another structurally related CCA, (E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-yl]morpholin-4-ium chloride (9a), possesses a similar pharmacological profile. Aim. To investigate the pharmacological activity of compound 9a in rats and mice. Materials and methods. The pharmacological activity profile of compound 9a was predicted using pharmaco-EEG in outbred male rats. The training set used to classify the action profile of the test compound consisted of EEG-effect matrices from 10 pharmacological agents: the NMDA antagonist dizocilpine, the D2/D3 antagonists haloperidol and sulpiride, the M-cholinoblocker tropicamide, the H1/5-HT2A receptor blocker hydroxyzine, the acetylcholinesterase inhibitor galantamine, the alpha-2 adrenoceptor agonist dexmedetomidine, the GABA mimetics aminophenylbutyric acid (phenibut) and bromdihydrochlorophenylbenzodiazepine (phenazepam), and the adenosine receptor antagonist caffeine. The prediction and classification results were validated in behavioral tests, including "Apomorphine-induced climbing", "5-HTP-induced hyperkinesis", the "Elevated plus maze" (EPM), and "Stress-induced hyperthermia" (SIH) in male outbred white mice. Results and discussion. Compound 9a at a dose of 10 mg/kg exerted almost no effect on the ECoG signal in rats. Increasing the dose to 20 and 50 mg/kg resulted in an EEG effect profile similar to those of hydroxyzine and sulpiride. In experiments on mice, compound 9a at doses of 10, 20, 50, and 100 mg/kg had no effect on the severity of apomorphine-induced climbing behavior. In the 5-HTP-induced hyperkinesis test, the test compound at a dose of 20 mg/kg significantly reduced the number of head twitches. At the same dose, compound 9a attenuated the hyperthermic response in animals during the first 20 minutes of the SIH test, but induced no behavioral changes in the EPM test. Conclusion. The classification results of the EEG effects in rats across various doses of 9a, along with the reduction in 5-HTP-induced responses in mice, suggest that the test molecule possesses 5-HT2A-blocking activity. A potential D2-blocking effect, hypothesized from the similarity of its EEG profiles to that of sulpiride, may also contribute to the central effects of the compound; however, this requires further investigation.