Emirace (nemonapride) / Astellas - LARVOL DELTA

Exploring the impact of deleterious missense nonsynonymous single nucleotide polymorphisms in the DRD4 gene using computational approaches. (PubMed, Sci Rep) - "We also found the V116D-nemonapride complex as structurally damaging; however, the interaction patterns of nemonapride were less altered in the MMPBSA analysis. Overall, this study revealed five novel deleterious variants along with a comprehensive understanding of their effect in the presence of an agonist and antagonist, which could be helpful for understanding disease susceptibility, precision medicine, and developing potential drugs."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Effects of dopamine receptor antagonists and radiation on mouse neural stem/progenitor cells. (PubMed, Radiother Oncol) - "We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exists, making it a novel combination therapy against glioblastoma. Normal tissue toxicity following this treatment scheme likely differs depending on age and sex and should be taken into consideration when designing clinical trials."

Journal • Preclinical • Alzheimer's Disease • Brain Cancer • CNS Tumor • Cognitive Disorders • Glioblastoma • Glioma • Oncology • Pediatrics • Solid Tumor • NES

Agonistic properties of a series of psychotropic drugs at 5-HT receptors in rat and human brain membranes determined by [S]GTPγS binding assay. (PubMed, Pharmacol Rep) - "Our previous studies have raised the concept of a psychoactive drug group with a common pharmacological mechanism of action, i.e., 5-HT receptor agonism, consisting of perospirone, aripiprazole, ziprasidone, clozapine, quetiapine, nemonapride, and trazodone. The present study demonstrates the data indicating that brexpiprazole and probably vortioxetine are included in this drug group. Lurasidone and asenapine are excluded from this group."

Journal • Preclinical

Interaction of the preferential D agonist (+)PHNO with dopamine D-D receptor heterodimers and diverse classes of monoamine receptors: Relevance for PET imaging. (PubMed, Eur J Pharmacol) - "In binding assays with membranes derived from cells co-expressing hD and hD receptors and labeled with [H]-Nemonapride or [H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hDor hD receptors, suggesting that (+)PHNO promotes formation of hD-hD heterodimers...In conclusion, PHNO is a potent agonist at hD., h5-HT and h5-HT as well as hD and hD receptors, and it potently activates dopamine hD-hD heterodimers. These interactions should be considered when interpreting PET studies with [C]-(+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Inhibitory Effects of Antipsychotics on the Contractile Response to Acetylcholine in Rat Urinary Bladder Smooth Muscles. (PubMed, Biol Pharm Bull) - "Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10 M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Psychiatry • Schizophrenia

In Silico Repositioning of Dopamine Modulators with Possible Application to Schizophrenia: Pharmacophore Mapping, Molecular Docking and Molecular Dynamics Analysis. (PubMed, ACS Omega) - "To do so, we have used the crystal structure of the D2-like dopamine receptor in complex with risperidone, eticlopride, and nemonapride. Linagliptin, citalopram, flunarizine, sildenafil, minocycline, and duloxetine were the drugs that best fit with our model...Flunarizine is a frequently used medication to treat migraines and vertigo. However, its antipsychotic properties have been previously hypothesized, particularly because of its possible ability to block the D2 dopamine receptors."

Journal • CNS Disorders • Migraine • Otorhinolaryngology • Psychiatry • Schizophrenia • Vertigo • DRD2

Recent findings leading to the discovery of selective dopamine D receptor ligands for the treatment of widespread diseases. (PubMed, Eur J Med Chem) - "The recently resolved crystal structures of DR in complexes with the potent ligands nemonapride and L-745870 strongly improved the knowledge on the molecular mechanisms involving the DR functions and may help medicinal chemists in drug design. This review is focused on the recent development of the subtype selective DR ligands belonging to classical or new chemotypes. Moreover, ligands showing functional selectivity toward G protein activation or β-arrestin recruitment and the effects of selective DR ligands on the above-mentioned diseases are discussed."

Journal • Review • CNS Disorders • Cognitive Disorders • Erectile Dysfunction • Mental Retardation • Movement Disorders • Oncology • Parkinson's Disease • Psychiatry

The Significance of Halogen Bonding in Ligand-Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D Receptor. (PubMed, Molecules) - "Thus, a set of molecular dynamics simulations for the dopamine D receptor, recently crystallized with the antipsychotic drug nemonapride (5WIU), and the five XSAR sets were performed to verify the identified hot spots for halogen bonding, in other words, primary (V5x40), and secondary (S5x43, S5x461 and H6x55). The simulations confirmed the key role of halogen bonding with V5x40 and H6x55 and supported S5x43 and S5x461. The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligand-receptor complex by halogen bonding."

Journal • CNS Disorders

Chemotactic migration of newly excysted juvenile Clonorchis sinensis is suppressed by neuro-antagonists. (PubMed, PLoS Negl Trop Dis) - "The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP)...Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct."

Journal

Structure based drug discovery for designing leads for the non-toxic metabolic targets in multi drug resistant Mycobacterium tuberculosis. (PubMed, J Transl Med) - "We propose an integrated approach of systems and structural biology for identifying targets that address the high attrition rate issue in lead identification and drug development We expect that this system level analysis will be applicable for identification of drug candidates to other pathogenic organisms as well."

Journal

TARGETING LYSOSOMES AS A POTENTIAL THERAPEUTIC APPROACH FOR T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA (EHA 2019) - "...The effect on lysosomes and autophagy was determined using the lysotracker and CytoID stainings by flow cytometry and fluorescence microscopy.Results Among all subtype-specific dopamine receptor modulators, only antagonists specific for dopamine receptor type 4 (DR4) (L741-742, Nemonapride, RBI 257) significantly reduced cell viability in T-ALL cells in the low microMolar range, while no effect on healthy cells was observed...Interestingly, these drugs have little effects in healthy blood cells. Therefore, our results support the further preclinical development of these drugs as potential treatments for T-ALL."