Depression is a serious and prevalent mood disorder that can dramatically affect the quality of life of patients suffering from the disease. In recent years, effective pharmacological treatments have been developed that are effective in many patients and have good safety profiles. For example, Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), for example, are widely used and have improved the quality of life of many patients. However, it has been estimated that as many as 30% of patients do not respond adequately to these marketed antidepressant agents. In addition, adverse effects experienced by some patients limit the use of currently available drugs. Therefore, while advances have been made, there is a significant population of patients who require novel treatment options. It is well known that the majority of antidepressants affect parameters of the sleep-wake cycle and circadian rhythms by increasing the latency of and suppressing REMS. This overlap in pharmacology led investigators to evaluate the impact of antagonizing 5-HT7 receptors in in vivo models of depression. The forced swim test (FST) and the tail suspension test (TST) are behavioral models that are routinely used to evaluate potential antidepressant agents. Interestingly, 5-HT7(-/-) mice exhibit reduced immobility times in both the FST and the TST. These findings stimulated further research into the impact of pharmacological blockade of 5-HT7 in these assays. Specifically, the selective 5-HT7 antagonists SB-269970 and JNJ-18038683 have been shown to induce antidepressant-like activity. SB-269970 induced a reduction in immobility time in both the FST and the TST in mice and rats. Similar results were observed in the TST model when mice were treated with JNJ-18038683. In addition, SB-269970 demonstrated a significantly faster antidepressant response in olfactory bulbectomized rats when compared to fluoxetine. These data suggest that the 5-HT7 receptor is a promising target for the development of antidepressant agents. We recently identified a novel series of highly selective 5-HT7 antagonists possessing drug-like properties. The binding data, physicochemical properties, and in vitro ADME data for this series of novel 5-HT7 selective ligands will be discussed. The pharmacokinetic data for compound(s) selected to undergo animal models of depression will also be presented.

Preliminary evaluation of novel serotonin antagonists as potential antidepressant agents

256th National Meeting (2018)

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