Correction To: TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP- 363856

Saarinen, Marcus; Mantas, Ioannis; Flais, Ivana; Ågren, Richard; Sahlholm, Kristoffer; Millan, Mark J.; Svenningsson, Per

doi:10.1038/s41386-022-01504-0

Cited by 2 publications

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“…Recent studies have reported SEP-856 to have a significant inhibitory effect on baseline locomotion in wild-type mice but not in TAAR1-knockout mice. Furthermore, the ability of SEP-856 to increase sensorimotor gating depends on TAAR1 (Saarinen et al, 2022). These results demonstrated the role of TAAR1 agonism in schizophrenia treatment.…”

Section: Discussionmentioning

confidence: 59%

“…An agonist of the TAAR1 receptor, SEP-856, was discovered through an in vivo phenotypic drug discovery approach and has shown efficacy in phase-II clinical trials for treating schizophrenia. SEP-856 has been shown to reduce phencyclidine-induced hyperactivity and improve deficits in social interaction and pre-pulse inhibition in preclinical studies (Dedic et al, 2019;Saarinen et al, 2022). Another TAAR1 agonist, RG7906, is also in phase-II clinical trials for schizophrenia treatment.…”

Section: Introductionmentioning

confidence: 99%

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Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment

Lü

Wang

et al. 2023

Front. Pharmacol.

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Introduction: Schizophrenia is a serious mental illness that requires effective treatment with minimal adverse effects. As preclinical and clinical research progresses, trace amine-associated receptor 1 (TAAR1) is becoming a potential new target for the treatment of schizophrenia.Methods: We used molecular docking and molecular dynamics (MD) simulations to discover TAAR1 agonists. The agonistic or inhibitory effects of compounds on TAAR1, 5-HT1A, 5-HT2A, and dopamine D2-like receptors were determined. We used an MK801-induced schizophrenia-like behavior model to assess the potential antipsychotic effects of compounds. We also performed a catalepsy assay to detect the adverse effects. To evaluate the druggability of the compounds, we conducted evaluations of permeability and transporter substrates, liver microsomal stability in vitro, human ether-à-go-go-related gene (hERG), pharmacokinetics, and tissue distribution.Results: We discovered two TAAR1 agonists: compounds 50A and 50B. The latter had high TAAR1 agonistic activity but no agonistic effect on dopamine D2-like receptors and demonstrated superior inhibition of MK801-induced schizophrenia-like behavior in mice. Interestingly, 50B had favorable druggability and the ability to penetrate the blood-brain barrier (BBB) without causing extrapyramidal symptoms (EPS), such as catalepsy in mice.Conclusion: These results demonstrate the potential beneficial role of TAAR1 agonists in the treatment of schizophrenia. The discovery of a structurally novel TAAR1 agonist (50B) may provide valuable assistance in the development of new treatments for schizophrenia.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment

Lü

Wang

et al. 2023

Front. Pharmacol.

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Identification and Characterization of ML321: a Novel and Highly Selective D2Dopamine Receptor Antagonist with Efficacy in Animal Models that Predict Atypical Antipsychotic Activity

Free¹,

Nilson²,

Boldizsar³

et al. 2022

Preprint

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We have developed and characterized a novel D2R antagonist with extreme GPCR selectivity; ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R, and to a lesser extent the D3R, demonstrating exceptional GPCR selectivity. The extreme D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in nonhuman primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dosedependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3R-mediated response (yawning) using the same dose of drug, thus indicating excellent in vivo selectivity. We also investigated the effects of ML321 in animal models that are predictive of antipsychotic efficacy in humans. We found that ML321 attenuates both amphetamine- and phencyclidine induced locomotor activity and restored pre-pulse inhibition (PPI) of acoustic startle in a dosedependent manner. Surprisingly, using doses that were maximally effective in both the locomotor and PPI studies, ML321 was relatively ineffective in promoting catalepsy. Kinetic studies revealed that ML321 exhibits slow-on and fast-off receptor binding rates, similar to those observed with atypical antipsychotics with reduced extrapyramidal side effects. Taken together, these observations suggest that ML321, or a derivative thereof, may exhibit "atypical" antipsychotic activity in humans with significantly fewer side effects than observed with currently FDA-approved D2R antagonists.

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Correction To: TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP- 363856

Cited by 2 publications

References 0 publications

Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment

Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment

Identification and Characterization of ML321: a Novel and Highly Selective D2Dopamine Receptor Antagonist with Efficacy in Animal Models that Predict Atypical Antipsychotic Activity

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