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Older and even new antidepressants cause adverse effects, such as orthostatic hypotension, hyper- or hypoglycemia, liver injury or lipid disorders. In our previous experiments we showed significant antidepressant- and anxiolytic-like activities of dual 5-HT1A and 5-HT7 antagonists with α1-adrenolitic properties i.e. 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15). Here, we evaluated the influence of chronic administration of HBK-14 and HBK-15 on blood pressure (non-invasive blood pressure measurement system for rodents), lipid profile (total cholesterol, low density lipoproteins-LDL, high density lipoproteins-HDL, triglycerides), glucose level, and liver enzymes activity (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase). We determined potential antihistaminic (isolated guinea pig ileum) and antioxidant properties (ferric reducing ability of plasma-FRAP, non-protein thiols-NPSH, stable free radical diphenylpicrylhydrazyl-DPPH) cytotoxicity. Our experiments revealed that HBK-14 and HBK-15 did not influence blood pressure, lipid profile, glucose level or liver enzymes activity in rats after 2-week treatment. We also showed that none of the compounds possessed antioxidant or cytotoxic properties at antidepressant- and anxiolytic-like doses. HBK-14 and HBK-15 very weakly blocked H1 receptors in guinea pig ileum. Positive results of our preliminary experiments on the safety of HBK-14 and HBK-15 encourage further studies concerning their effectiveness in the treatment of depression and/or anxiety disorders.

The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity.

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14-FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15-FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.