D-neuron, ligand neuron of trace amine-associated receptor 1 (TAAR1): Key of novel non-D2 receptor-binding antipsychotics

2021 ◽  
Vol 1 (1) ◽  
pp. 031-038
Author(s):  
Keiko Ikemoto
Keyword(s):  
Receptor Binding ◽  
Molecular Basis ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Immunohistochemical Method ◽  
Post Mortem ◽  
Related Substances ◽  
Trace Amine ◽  
D Cell ◽  
Human Brains

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though failed to find in the homologous area of monkey brains. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. The number of D-neuron in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. I proposed “D-cell hypothesis of schizophrenia”, that NSC dysfunction-based D-neuron reduction is cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, progressive pathophysiology and prospectiveness of TAAR1 medicinal chemistry, emphasizing importance of D-neuron.

“D-cell hypothesis of schizophrenia”: Background theory of Novel non-D2 receptor medicinal chemistry

2021 ◽  
Vol 3 (1) ◽  
pp. 033-040
Author(s):  
Keiko Ikemoto
Keyword(s):  
Medicinal Chemistry ◽  
Partial Agonist ◽  
D2 Receptor ◽  
Immunohistochemical Method ◽  
Post Mortem ◽  
Background Theory ◽  
Related Substances ◽  
Post Mortem Brain ◽  
Receptor Profile ◽  
D Cell

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. Characteristic receptor profile of the compound is shown to be trace amine-associated receptor 1 (TAAR1) full agonist and 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), an antipsychotic acting site, of human brain, though failed to find in the homologous area of monkey. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. Number of D-neurons in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. “D-cell hypothesis of schizophrenia”, which I proposed based on this post-mortem brain study, that NSC dysfunction-induced D-neuron reduction as cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, showing progressive pathophysiology of schizophrenia, has been proved to be a predictive hypothesis for TAAR1 medicinal chemistry.

scholarly journals D-Cell Hypothesis (Trace Amine Hypothesis) of Schizophrenia, and importance of Trace Amine-Associated Receptor, Type 1 (TAAR1)

2015 ◽  
pp. 1-5
Author(s):  
Keiko Ikemoto
Keyword(s):  
Molecular Basis ◽  
Therapeutic Strategies ◽  
Immunohistochemical Method ◽  
Trace Amine ◽  
D Cell ◽  
Postmortem Brains ◽  
Novel Therapeutic Strategies ◽  
D2 Antagonists ◽  
Novel Therapeutic

Mesolimbic dopamine (DA) hyperactivity is a well-known pathophysiological hypothesis of schizophrenia. The author shows a hypothesis to clarify the molecular basis of mesolimbic DA hyperactivity of schizophrenia. An immunohistochemical method was used to show D-neuron (trace amine (TA) neuron) decrease in the nucleus accumbens (Acc) of postmortem brains with schizophrenia. The striatal D-neuron decrease in schizophrenia and consequent (TAAR1) stimulation decrease onto terminals of midbrain ventral tegmental area (VTA) DA neurons induces mesolimbic DA hyperactivity of schizophrenia. Dysfunction of subventricular neural stem cells (NSC), located partially overlapping Acc is the cause of D-neuron decrease in Acc. DA hyperactivity, which inhibits NSC proliferation, causes disease progression of schizophrenia. The highlight is the rational that the “D-cell hypothesis (TA hypothesis) of schizophrenia” is a pivotal theory to link NSC dysfunction hypothesis to DA hypothesis. From a therapeutic direction, (1) TAAR1 agonists, (2) DA D2 antagonists, and (3) neurotrophic substances have potential to normalize mesolimbic DA hyperactivity. To develop novel therapeutic strategies, metabolisms of TAAR1 ligands, and NSC- and D-neuron-pathophysiology of neuropsychiatric illnesses should further be explored.

Effect of amphetamine on dopamine D2 receptor binding in the primate brain with the agonist ligand [11C]MNPA

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S646-S646
Author(s):  
Nicholas Seneca ◽  
Sjoerd Finnema ◽  
Masanori Ichise ◽  
Balazs Gulyas ◽  
Håkan Wikstrom ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D2 ◽  
Primate Brain

2-Phenyl-4-(aminomethyl)imidazoles as Potential Antipsychotic Agents. Synthesis and Dopamine D2 Receptor Binding

1995 ◽  
Vol 38 (12) ◽  
pp. 2251-2255 ◽  
Author(s):  
Andrew Thurkauf ◽  
Alan Hutchison ◽  
John Peterson ◽  
Linda Cornfield ◽  
Robin Meade ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Antipsychotic Agents ◽  
Dopamine D2

Early life exposure to poly I:C impairs striatal DA-D2 receptor binding, myelination and associated behavioural abilities in rats

2021 ◽  
pp. 102035
Author(s):  
Brijendra Singh ◽  
Yogesh Kumar Dhuriya ◽  
Nisha Patro ◽  
Mahendra Kumar Thakur ◽  
Vinay Kumar Khanna ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Early Life ◽  
D2 Receptor ◽  
Poly I:C ◽  
Early Life Exposure

scholarly journals Strong evolutionary convergence of receptor-binding protein spike between COVID-19 and SARS-related coronaviruses

2020 ◽  
Author(s):  
Yonghua Wu
Keyword(s):  
Receptor Binding ◽  
Molecular Basis ◽  
Acid Sites ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Partner Protein ◽  
Evolutionary Convergence ◽  
Genome Level ◽  
Phenotypic Convergence

AbstractCoronavirus Disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS)-related coronaviruses (e.g., 2019-nCoV and SARS-CoV) are phylogenetically distantly related, but both are capable of infecting human hosts via the same receptor, angiotensin-converting enzyme 2, and cause similar clinical and pathological features, suggesting their phenotypic convergence. Yet, the molecular basis that underlies their phenotypic convergence remains unknown. Here, we used a recently developed molecular phyloecological approach to examine the molecular basis leading to their phenotypic convergence. Our genome-level analyses show that the spike protein, which is responsible for receptor binding, has undergone significant Darwinian selection along the branches related to 2019-nCoV and SARS-CoV. Further examination shows an unusually high proportion of evolutionary convergent amino acid sites in the receptor binding domain (RBD) of the spike protein between COVID-19 and SARS-related CoV clades, leading to the phylogenetic uniting of their RBD protein sequences. In addition to the spike protein, we also find the evolutionary convergence of its partner protein, ORF3a, suggesting their possible co-evolutionary convergence. Our results demonstrate a strong adaptive evolutionary convergence between COVID-19 and SARS-related CoV, possibly facilitating their adaptation to similar or identical receptors. Finally, it should be noted that many observed bat SARS-like CoVs that have an evolutionary convergent RBD sequence with 2019-nCoV and SARS-CoV may be pre-adapted to human host receptor ACE2, and hence would be potential new coronavirus sources to infect humans in the future.

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