The Extracellular Entrance Provides Selectivity to Serotonin 5‑HT₇ Receptor Antagonists with Antidepressant-like Behavior in Vivo

The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT₇R antagonist <b>6</b> endowed with high affinity (<i>K</i>_i = 0.7 nM) and significant 5-HT_1AR selectivity (ratio >1428). Compound <b>6</b> exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT₇R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders