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Structure-activity relationship of pyrazol-4-ylpyridine derivatives and identification of a radiofluorinated probe for imaging t.e muscarinic acetylcholine receptor M4

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Acta Pharmaceutica Sinica B 2023年第1期13卷 213-226页

作者： Ahmed Haider Xiaoyun Deng Olivia Mastromihalis Stefanie K.Pfister troels e.Jeppesen Zhiwei Xiao Vi Pham Shaofa Sun Jian Rong Chunyu Zhao Jiahui Chen Yinlong Li t.eresa R.Connors April t.Davenport James B.Daunais Vahid Hosseini Wenqing Ran Arthur Christopoulos Lu Wang celine Valant Steven H.Liang Depart.ent of Radiology Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical SchoolBostonMA 02114USA Depart.ent of Nuclear Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Drug Discovery Biology Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Neuromedicines Discovery Cent.e Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Hubei Collaborative Innovation Cent.e for Non-power Nuclear technology College of Nuclear Technology&Chemistry and BiologyHubei University of Science and TechnologyXianning 437100China Depart.ent of Neurology Massachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Depart.ent of Physiology and Pharmacology Wake Forest School of MedicineWinston SalemNC 27157USA terasaki Institute for Biomedical Innovation(tIBI) Los AngelesCA 90024USA Center of Cyclotron and Pet Radiopharmaceuticals Department of Nuclear Medicine and PET/CT-MRI Centerthe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China

t.ere is an accumulating body of evidence implicating t.e muscarinic acetylcholine receptor4(M4)in schizophrenia and dementia with Lewy bodies,however,a clinically validated M4positron emission tomography(Pet)radioligand is currently *** such,t.e aim of this study was to develop a suitable M4Pet ligand that allows t.e non-invasive visualization of M4in t.e ***-activity relationship studies of pyrazol-4-yl-pyridine derivates led to t.e discovery of target compound 12—a subtype-selective positive allosteric modulator(PAM).t.e radiofluorinated analogue,[18F]12,was synt.esized in 28±10%radiochemical yield,>37 GBq/μmol and an excellent radiochemical purity>99%.Initial in vitro autoradiograms on rodent brain sections were performed in t.e absence of carbachol and showed moderate specificity as well as a low selectivity of[18F]12 for t.e M4-rich ***,in t.e presence of carbachol,a significant increase in tracer binding was observed in t.e rat striatum,which was reduced by>60%under blocking conditions,thus indicating that orthosteric ligand interaction is required for efficient binding o f[18F]12 to t.e allosteric ***,however,t.e presence of carbachol was not required for high specific binding in t.e non-human primate(NHP)and human striatum,and did not furt.er improve t.e specificity and selectivity of[18F]12 in higher *** results pointed towards significant species-differences and paved t.e way for a preliminary Pet study in NHP,where peak brain uptake of[18F]12 was found in t.e putamen and temporal *** conclusion,we report on t.e identification and preclinical development of t.e first radiofluorinated M4Pet radioligand with promising *** availability of a clinically validated M4Pet radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

关键词： Muscarinicacetylcholine receptor Positronemission tomography Neuroimaging Neuropharmacology Neurological disorders

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Safety and tolerability of edivoxetine for Long-term t.eat.ent of Major Depressive Disorder in Adult Pat.ents

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Open Journal of Psychiatry 2014年第2期4卷 131-140页

作者： tina M. Oakes James M. Martinez Mary Anne Dellva celine Goldberger Beth A. Pangallo Mark e. Bangs Jonna Ahl William B. White eli Lilly and Company Indianapolis USA University of Connecticut School of Medicine Farmington USA

this 12-month open-label, but dose-blinded extension phase, evaluated t.e safety and tolerability of flexibly-dosed edivoxetine (6, 9, 12 or 18 mg once daily) in pat.ents (N = 397) with major depressive disorder, who completed t.e 10-week randomized, double-blind, placebo-controlled acute phase of t.e *** pat.ents were t.eated with edivoxetine during t.e extension phase. t.e mean age of t.e pat.ents was 45 years, and most were white females. Safety evaluations included assessment of t.eat.ent.emergent adverse events (teAes), laboratory and vital sign measures, and suicidality. Within-group t-tests based on a 2-sided significance level of 0.05 and 95% confidence levels were used to assess whet.er changes from baseline were statistically significant from zero. t.e overall completion rate was 54%. Adverse event was t.e most common (14.4%) reason for discontinuation, which included blood pressure increased (1.3%), heart rate increased (1.3%), anxiety (1.0%), and tachycardia (1.0%). At least 1 teAe was reported by 72.3% of pat.ents, of which headache (10.8%) and hyperhidrosis (10.1%) were t.e most common;2.8% of pat.ents had ≥1 serious adverse events, and t.ere were no completed suicides. No clinically relevant changes were observed in most laboratory measures. Potentially clinically significant changes in ALt values occurred in 1.8% of pat.ents, and eit.er normalized or had decreased by t.e last assessment. Mean increases in blood pressure and pulse were consistent with those observed in t.e acute phase and appeared to reach a plateau within 3 to 5 months of t.eat.ent. In conclusion, safety and tolerability findings during this long-term extension phase evaluation of edivoxetine were consistent with its norepinephrine reuptake inhibition profile.

关键词： edivoxetine Norepinephrine Major Depressive Disorder Safety tolerability

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Comparative effects of α2δ-1 ligands in mouse models of colonic hypersensitivity

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World Journal of Gastroenterology 2016年第31期22卷 7111-7123页

作者： Mathieu Meleine Ludivine Boudieu Agat.e Gelot.emilie Muller Amandine Lashermes Julien Matricon celine Silberberg Vassilia t.eodorou Alain eschalier Denis Ardid Frederic A Carvalho Clermont Université Université d'Auvergne INSERM 1107 Neuro-Dol Université d’Auvergne INSERM 1107 Neuro-Dol INRA EI-Purpan UMR 1054 Neuro-Gastroenterology and Nutrition

AIM: to investigate anti-hypersensitive effects of α2δ-1 ligands in non-inflammatory and inflammationassociated colonic hypersensitivity(CHS) mouse ***: to induce an inflammation-associated CHS, 1% dextran sulfate sodium(DSS) was administered to C57Bl/6J male mice, in drinking water, for 14 d. Regarding t.e non-inflammatory neonatal maternal separation(NMS)-induced CHS model, wild-type C57BI/6J pups were isolated from t.eir mot.er from day 2 to day 14(P2 to P14), three hours per day(from 9:00 a.m. to 12:00 p.m.). Colorectal distension was performed by inflating distension probe from 20 μL to 100 μL by 20 μL increment step every 10 s. After a first colorectal distension(CRD), drugs were administered subcutaneously, in a cumulative manner,(Gabapentin at 30 mg/kg and 100 mg/kg; Pregabalin at 10 mg/kg and 30 mg/kg; Carbamazepine at 10 mg/kg and 30 mg/kg) and a second CRD was performed one hour after each ***: t.e visceromotor response(VMR) to CRD was increased by our NMS paradigm protocol in comparison to non-handled(NH) mice, considering t.e highest distension volumes(80 μL: 0.783 ± 0.056 mV /s vs 0.531 ± 0.034 m V/s, P e, respectively). In t.e inflammationassociated CHS, DSS-t.eated mice showed a dramatic and significant increase in VMR at 60 and 80 μL distension volumes when compared to control mice(60 μL: 0.920 ± 0.079 m V/s vs 0.426 ± 0.100 m V/s P ter-t.eated mice, respectively). Carbamazepine failed to significantly reduce CHS in both models. Gabapentin significantly reduced CHS in t.e DSS-induced model for both subcutaneous injections at 30 or 100 mg/kg. Pregabalin s i g n i f i c a n t l y r e d u c e d V M R t o C R D i n t h e n o n-inflammatory NMS-induced CHS model for t.e acute subcutaneous administration of t.e highest cumulative dose(30 mg/kg) and significan

关键词： Neonatal maternal separation Dextran sulfate sodium Colonic hypersensitivity mouse models Colorectal distension α2δ-1 ligands

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