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Journal: Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-D-aspartate receptors. (Pubmed Central) - Aug 24, 2024 These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore synaptic plasticity by reducing activity-dependent CDI.
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Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.
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Journal: Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons. (Pubmed Central) - Jun 24, 2021 Furthermore, cell-type-specific knockdown of GluN2B-containing NMDARs in mPFC demonstrates that GluN2B subunits on excitatory, but not inhibitory, neurons are necessary for antidepressant-like effects of AGN-241751. Together, these results demonstrate antidepressant-like actions of the NMDAR PAM AGN-241751 and identify GluN2B on excitatory neurons of mPFC as initial cellular trigger underlying these behavioral effects.
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Trial completion: AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - Dec 12, 2019 P1/2, N=223, Completed, Together, these results demonstrate antidepressant-like actions of the NMDAR PAM AGN-241751 and identify GluN2B on excitatory neurons of mPFC as initial cellular trigger underlying these behavioral effects. Active, not recruiting --> Completed
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Phase classification, Enrollment change, Trial completion date, Trial primary completion date: AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - Jun 5, 2019 P1/2, N=220, Active, not recruiting, Active, not recruiting --> Recruiting Phase classification: P1 --> P1/2 | N=100 --> 220 | Trial completion date: May 2019 --> Oct 2019 | Trial primary completion date: May 2019 --> Oct 2019
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Enrollment closed: AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - May 10, 2019 P1, N=100, Active, not recruiting, Phase classification: P1 --> P1/2 | N=100 --> 220 | Trial completion date: May 2019 --> Oct 2019 | Trial primary completion date: May 2019 --> Oct 2019 Recruiting --> Active, not recruiting
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