Discovery of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 2-(5-(4′-Chloro-[1,1′-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders

Krasavin, Mikhail; Lukin, Alexey; Sukhanov, I.; Gerasimov, Andrey; Kuvarzin, Savelii R.; Efimova, Evgeniya V.; Дорофейкова, Мария; Nichugovskaya, Anna; Matveev, A. V.; Onokhin, Kirill; Zakharov, Konstantin; Gainetdinov, Raul R.

doi:10.3390/biom12111650

Cited by 4 publications

(1 citation statement)

References 40 publications

(63 reference statements)

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“…Second, it could be questioned if and how non-canonical mechanisms can be pragmatically tackled for the development of novel therapeutic strategies that are needed for those conditions, such as TRS, that do not respond or respond poorly to the available antipsychotics. In this regard and concerning presynaptic dopamine regulation, at least two compounds are in an advanced phase of clinical development represented by TAAR1 agonist [ 174 , 582 , 583 , 584 , 585 ] and xanomeline + trospium [ 168 , 169 , 585 , 586 ], both involved in the regulation of dopamine release, though not through a primary dopamine-dependent receptor mechanism. Furthermore, regarding the modulation of synaptic proteins that are a significant non-canonical dopamine-dependent effect of antipsychotics, it should be acknowledged that despite the technical difficulties, there is a growing interest in the possibility of interfering with the PSD proteins’ function.…”

Section: Discussionmentioning

confidence: 99%

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Bartolomeis¹,

Ciccarelli²,

Simone³

et al. 2023

IJMS

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Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics’ receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na2+ channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.

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