Cell
May 11, 2023
Isha Singh, Anubha Seth, Christian B Billesbølle et al.
97 citations
Docking over 200 million small molecules against the inward-open state of the serotonin transporter (SERT) identified two potent, low-nanomolar inhibitors that stabilize an outward-closed conformation. These compounds showed little activity against common off-targets, and a cryo-EM structure confirmed the predicted binding geometry. In mouse behavioral assays, both compounds exhibited anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold greater than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. The work suggests a promising path toward new treatments for depression, anxiety, and addiction with improved safety.
Frontiers in molecular biosciences
January 1, 2023
Vladimir M Pogorelov, Ramona M Rodriguiz, Bryan L Roth et al.
26 citations
Lisuride, a drug that activates the serotonin 2A receptor but preferentially stimulates G protein over β-arrestin signaling, produced few hallucinogenic-like behaviors (head twitches) in mice, unlike LSD. In wild-type and β-arrestin knockout mice, lisuride reduced locomotion and rearing, increased then decreased grooming in βArr2 knockouts, and decreased serotonin syndrome responses especially in βArr2 knockouts. Prepulse inhibition was disrupted only in βArr1 knockouts at 0.5 mg/kg, and this effect was not reversed by a 5-HT2A antagonist but was normalized by clozapine and other drugs. In vesicular monoamine transporter 2 mice, lisuride reduced immobility in the tail suspension test and promoted sucrose preference for up to two days, suggesting antidepressant-like effects without hallucinogenic actions.
bioRxiv : the preprint server for biology
June 5, 2023
Vladimir M Pogorelov, Ramona M Rodriguiz, Bryan L Roth et al.
4 citations
preprint
Lisuride, a drug that activates the serotonin 2A receptor without causing hallucinations, reduced locomotion and rearing in mice but produced a U-shaped pattern of stereotypies. Head twitches and retrograde walking were rare. Grooming decreased in β-arrestin1 knockout mice but showed a biphasic response in β-arrestin2 knockouts. Prepulse inhibition was disrupted by lisuride only in β-arrestin1 knockouts, and this effect was not reversed by a serotonin 2A antagonist but was normalized by a dopamine D2/D3 antagonist in wild-type mice. Lisuride also reduced immobility in the tail suspension test and increased sucrose preference for up to two days, suggesting antidepressant-like effects without hallucinogenic activity.