Synthesis and evaluation of novel 5-HT2A receptor inverse agonist with excellent in vivo antipsychotic efficacy and superior tissue distribution for treatment of Parkinson's disease psychosis

Article

作者: Yang, Huijie ; Ma, Mingxu ; Xu, Hengwei ; Wei, Yingjie ; Zhang, Jianzhao ; Zhu, Xiaoyin ; Ye, Liang ; Du, Guangying ; Tian, Jingwei ; Dai, Yusen ; Gao, Yonglin ; Zhao, Min ; Wang, Wenyan

Pimavanserin is a 5-HT_2A receptor inverse agonist as the first and only drug approved for the treatment of Parkinson's disease psychosis (PDP), which has a black box warning regarding an increased risk of death in elderly patients with dementia-related psychosis and warning related to QTc interval prolongation. In this article, a total of 25 novel modulated pimavanserin derivatives were designed and synthesized. The optimal compound P25a exhibited better 5-HT_2A receptor inverse agonist activity and lower hERG inhibition than that of pimavanserin. Molecular dynamics simulations also indicated that compound P25a had a more stable binding mode with the receptor. Moreover, compound P25a exhibited almost 2.2-fold AUC_last increasement in in vivo pharmacokinetics study with higher exposure in brain and lower distribution in cardiac tissue. Compound P25a demonstrated higher functional activities in both DOI-induced head twitches model and MK801-induced hyperactivity model. In conclusion, the enhanced in vitro and in vivo efficacy profiles, minimal hERG inhibition, and superior tissue distribution, established compound P25a as a promising preclinical candidate for treatment of PDP that warranted further investigation.

2025-10-09·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Highly Selective 5-HT_2A Agonists Using Structure-Guided Design

Article

作者: McKee, John L. ; Cavalco, Natalie G. ; Schalk, Serena S. ; Cuccurazzu, Bruna ; Bonniwell, Emma M. ; Shacham, Naomi ; Lammers, Josie C. ; Halberstadt, Adam L. ; Fenske, Tyler G. ; McCorvy, John D.

With a resurgence in interest in psychedelics as rapid-acting and durable neuroplastic therapies, there is a critical need to develop more selective 5-HT_2A agonists to investigate the basic neurobiological mechanisms of psychedelics. Here, we show that selectivity for 5-HT_2A over the closely related 5-HT_2C receptor can be leveraged using structure-based design to target residue L123^2.53 in transmembrane 2 (TM2) of the extended binding pocket by increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. Furthermore, we comprehensively confirm selectivity at 5-HT_2C RNA editing isoforms, TM2 reciprocal 5-HT_2A and 5-HT_2C mutants, and mouse 5-HT_2A and 5-HT_2C orthologs, to form a complete profile for highly selective 5-HT_2A agonists to date. Using a combination of structure-activity relationships, molecular docking, and mouse head-twitch response assays, we show that 5-HT_2A-selective agonists can be rationally designed to improve 5-HT_2A target engagement, further advancing the study into the neurobiological mechanisms of psychedelic effects.

2025-07-01·Psychopharmacology

Effects of psilocybin, the 5-HT2A receptor agonist TCB-2, and the 5-HT2A receptor antagonist M100907 on visual attention in male mice in the continuous performance test

Article

作者: Fletcher, Paul J ; Rahbarnia, Arya ; Li, Zhaoxia

RATIONALE:

Neuropsychiatric disorders such as depression are characterized in part by attention deficits. Attention is modulated by the serotonin (5-HT) neurotransmitter system. The 5-HT_2A agonist and hallucinogen psilocybin (PSI) is a promising treatment for disorders characterized by attention changes. However, few studies have investigated PSI's direct effect on attention.

OBJECTIVE:

Using the rodent continuous performance task (CPT), we assessed PSI's effect on attention. We also evaluated the impact of 5-HT_2A receptor agonist TCB-2 and antagonist M100907 for comparative purposes.

METHODS:

In the CPT, mice learned to distinguish visual targets from non-targets for milkshake reward. Performance was then tested following injections of PSI (0.3, 1, and 3 mg/kg), TCB-2 (0.3, 1, and 3 mg/kg), or M100907 (0.1, 0.3, and 1 mg/kg). Subsequently, drug effects were then evaluated using a more difficult CPT with variable stimulus durations. Mice were then tested on the CPT following repeated PSI injections. Drug effects on locomotor activity were also measured.

RESULTS:

In the CPT, all three drugs reduced hit and false alarm rate and induced conservative responding. PSI also reduced target discrimination. These effects were seen primarily at doses that also significantly reduced locomotor activity. No drug effects were seen on the more difficult CPT or following repeated PSI injections.

CONCLUSIONS:

Psilocybin, TCB-2, and M100907 impaired performance of the CPT. However, this may be in part due to drug-induced locomotor changes. The results provide little support for the idea that psilocybin alters visual attention, or that 5-HT_2A receptors modulate this process.

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2024-05-13

·Firstwordpharma

AbbVie wagers up to $2B on Gilgamesh's approach to psychedelics – minus the trip

AbbVie is teaming up with Gilgamesh Pharmaceuticals in a deal worth up to $2 billion to develop a new class of drugs designed to treat psychiatric disorders without the psychoactive side effects that can be induced with first-generation psychedelics.The pharma will harness Gilgamesh's research platform to create neuroplastogens that mimic the therapeutic potential of classic psychedelics, while avoiding hallucinations and eliminating the need for in-office administration and supportive care.Already a heavyweight in neuroscience, AbbVie says there's still significant unmet need for people living with psychiatric disorders. "We know that to innovate in this field, we need to pursue novel technologies and approaches," said Jonathon Sedgwick, the company's global head of discovery research, adding that neuroplastogens could "pave the way for additional treatment approaches in psychiatry."According to AbbVie, neuroplastogens target mechanisms that have shown potential to provide significant clinical benefits while minimising the challenging effects seen with first-generation psychedelics. Gilgamesh's platform leverages complex behavioural models, electrophysiology and molecular measures of neuroplasticity, while machine learning algorithms help to systematically map the bioactivity of psychoactive compounds.AbbVie and Gilgamesh will research and develop a portfolio of next-generation therapeutics for psychiatric disorders. Gilgamesh will receive an upfront payment of $65 million and is eligible for up to $1.95 billion in option fees, milestones, and tiered royalties on net sales. Upon exercising its option, AbbVie will lead development and commercialisation activities.Gilgamesh's internal pipeline features one neuroplastogen: GM-5022, an oral non-hallucinogenic compound in early development for depression and anxiety. Its two lead programmes are GM-1020, an oral NMDA receptor antagonist, as well as the short-acting 5-HT2A agonist GM-2505, both of which have moved to Phase II in major depressive disorder. The company previously raised $27 million and $39 million in successive series A and B rounds.

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