HBK-14 and HBK-15, triple 5-HT1A, 5-HT7 and 5-HT3 antagonists with potent antidepressant- and anxiolytic-like properties, increase seizure threshold in various seizure tests in mice.

Most antidepressants lower seizure threshold, which might be due to the modulation of serotonergic neurotransmission. Here, we investigated the effects of two 5-HT1A, 5-HT7 and 5-HT3 antagonists, i.e., 1-(2-(2-(2,6-dimethylphenoxy)ethoxy)ethyl)-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-{2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15), with antidepressant- and anxiolytic-like properties, on seizure thresholds in three acute seizure tests, i.e., the intravenous pentylenetetrazole, maximal electroshock seizure threshold (MEST), and 6-Hz corneal stimulation test in mice. We also evaluated their affinity for voltage-gated sodium channels. Our results indicate that HBK-14 increased seizure thresholds in three seizure tests in mice, while HBK-15 was active in the MEST and 6-Hz tests. None of the compounds affected neuromuscular strength or motor coordination at active doses. We showed that both compounds had high affinity for voltage-dependent sodium channels, which combined with the influence on 5-HT1A, 5-HT7 and 5-HT3 receptors, might underlie their anticonvulsant effects. Since most antidepressants lower the seizure threshold, the fact that both compounds with potent antidepressant-like activity, increased or had no influence on seizure threshold is worth investigating.