HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats

Abstract

Anxiety is a common mental disorder, and its prevalence has lately increased because of the COVID-19 pandemic. Unfortunately, the available anxiolytics are often ineffective, and most possess addictive potential. Thus, searching for novel compounds is essential. In our previous studies, we selected a multimodal compound, HBK-15, which showed a fast antidepressant-like effect in animal models of depression. HBK-15 demonstrated a high affinity for serotonin 5-HT1A receptors and moderate for 5-HT7, dopamine D2, and α1-adrenoceptors. Based on the receptor profile and preliminary studies, we aimed to investigate the anxiolytic potential of HBK-15 using the conditioned-response rat model of anxiety, i.e., the Vogel drinking test. We performed hot plate and free-drinking tests to exclude false positive results in the Vogel test. Using radioligand binding studies, we also investigated the affinity of the compound for the selected biological targets, which play a role in anxiety. Our experiments revealed that HBK-15 showed an anxiolytic-like effect in rats (5 mg/kg) without influencing the pain threshold or the amount of water consumed in the free-drinking test. Furthermore, the tested compound did not show a significant affinity for the selected biological targets, which suggests that its anxiolytic-like mechanism of action could be connected with the interaction with other receptors. This study indicates that multimodal compounds with a receptor profile similar to HBK-15 could be an attractive therapeutic option for patients with a generalized anxiety disorder. However, more studies are required to determine the exact mechanism of action of HBK-15 and its safety profile.

HBK-15, a multimodal compound, induces procognitive effects through modulating hippocampal LTP and enhancing theta-gamma coupling in mice

“…Intriguingly, a review of HBK-15's receptor pro le indicates that its LTP induction could be NMDAindependent since HBK-15 did not bind to any of this receptor's sites. In addition, HBK-15 exhibited no a nity for AMPA, kainate, metabotropic glutamate, 5-HT3, and nicotinic receptors [71] or N-type voltagegated calcium channels (Cav2.2). However, HBK-15 showed a substantial a nity for the L-type voltagegated calcium channel (Cav1.2), a signi cant contributor to NMDA-independent LTP formation in the hippocampus (reviewed in [3]).…”

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

“…In the next step of our study, we investigated the anxiolytic-like activity of the tested compound in the four-plate, elevated plus maze, and marble-burying tests in mice. The modulation of the serotonin system, especially the blockade of 5-HT 1A and 5-HT 7 receptors, is involved in the anxiolytic-like effects of many compounds [ 22 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. The four-plate test is one of the most common tests for assessing the anxiolytic-like properties of novel compounds, and is based on the conflict situation when an electric shock inhibits a mouse’s natural tendency to explore a new environment.…”