Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT1A and 5-HT7 Antagonists in Animal Models

Abstract

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.

HBK-14 and HBK-15 Do Not Influence Blood Pressure, Lipid Profile, Glucose Level, or Liver Enzymes Activity after Chronic Treatment in Rats

“…We previously demonstrated that dual 5-HT 1A and 5-HT 7 antagonists (HBK-14 and HBK-15), which showed significant antidepressant- and anxiolytic-like activities [7], possessed α 1 -adrenolytic properties and lowered blood pressure in rats [8]. HBK-14 (but not HBK-15) showed hypotensive activity at antidepressant-like doses after acute treatment [8].…”

“…The doses of studied compounds were based on our previous experiments [7]. The blood pressure was measured three times a week (before and on the 3 rd , 5 th , 8 th , 11 th and 14 th day of administration).…”

“…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) showed significant antidepressant- and anxiolytic-like effects in mice and rats [7,8]. Both compounds lowered blood pressure after acute treatment [8].…”

Pharmacophore Comparison and Development of Recently Discovered Long Chain Arylpiperazine and Sulfonamide Based 5-HT7 Ligands

“…5), which showed high affinity for the 5-HT 7 receptor (K i = 156 nM, K i = 34 nM, respectively) but with poor selectivity over the 5-HT 1A receptor (K i = 41 nM, K i <1 nM, respectively), with antagonist activity at 5-HT 7 . 25 However, because both of these receptors are known to play a role in depression and anxiety, the compounds were tested in vivo. In the forced swim test, 2 (5.0 mg/kg) decreased immobility time by 38% compared to the vehicle and increased swimming behavior by 185%.…”

“…23 5-HT 7 R antagonists have demonstrated a variety of effects including stress reduction and antidepressant effects. 24,25 On the other hand, 5-HT 7 R agonists have been shown to inhibit nociceptive control, which could make them good candidates as analgesic drugs. 26 …”