Background Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on... Show moreBackground Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS).Methods Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers >= 1:10, thereof low titers as <= 1:100 and high titers as >1:100. We used the Center for Epidemiological Studies-Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points.Results NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1-4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (beta(crude) = 2.56 [95%CI = -0.34 to 5.45]; beta(adjusted) = 2.26 [95%CI = -0.68 to 5.20]) and effects were highest in patients with high titer (low titers: beta(crude) = 1.42 [95%CI = -1.79 to 4.62], beta(adjusted) = 0.53 [95%CI = -2.47 to 3.54]; high titers: beta(crude) = 5.85 [95%CI = 0.20 to 11.50]; beta(adjusted) = 7.20 [95%CI = 0.98 to 13.43]).Conclusion Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients. Show less
In this study, we determined the crystal structure of an engineered human adenosine A2A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist... Show moreIn this study, we determined the crystal structure of an engineered human adenosine A2A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies. Show less
Ortiz Zacarías, N.V.; Chahal, K.K.; Šimková, T.; Horst, C. van der; Zheng, Y.; Inoue, A.; ... ; Heitman, L.H. 2021
Covalently acting inhibitors constitute a large and growing fraction of approved small-molecule therapeutics as well as useful tools for a variety of in vitro and in vivo applications. Here, we... Show moreCovalently acting inhibitors constitute a large and growing fraction of approved small-molecule therapeutics as well as useful tools for a variety of in vitro and in vivo applications. Here, we aimed to develop a covalent antagonist of CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a therapeutic target in inflammation and immuno-oncology. Based on a known intracellularly binding CCR2 antagonist, several covalent derivatives were synthesized and characterized by radioligand binding and functional assays. These studies revealed compound 14 as an intracellular covalent ligand for CCR2. In silico modeling followed by site-directed mutagenesis confirmed that 14 forms a covalent bond with one of three proximal cysteine residues, which can be engaged interchangeably. To our knowledge, compound 14 represents the first covalent ligand reported for CCR2. Due to its unique properties, it may represent a promising tool for ongoing and future studies of CCR2 pharmacology. Show less
During the course of drug discovery translational steps are made. The translation from in vitro to in vivo experiments is not as predictive as one would desire, resulting in selection of... Show moreDuring the course of drug discovery translational steps are made. The translation from in vitro to in vivo experiments is not as predictive as one would desire, resulting in selection of inefficacious compounds but also in overlooking of promising drug candidates. This is not different for the mGlu2 receptor for which no drugs are available on the market so far despite enormous drug discovery efforts. Therefore, there is a need to improve the molecular understanding of key in vitro parameters that drive in vivo efficacy. Hence, this thesis focuses on the concepts of target binding kinetics and functional efficacy of both allosteric and orthosteric ligands of the mGlu2 receptor. Show less
Drug-discovery has become a complex disci- pline in which the amount of knowledge about human biology, physiology, and biochemistry have increased. In order to harness this complex body of... Show moreDrug-discovery has become a complex disci- pline in which the amount of knowledge about human biology, physiology, and biochemistry have increased. In order to harness this complex body of knowledge mathe- matics can play a critical role, and has actually already been doing so. We demonstrate through four case studies, taken from previously published data and analyses, what we can gain from mathematical/analytical techniques when nonlinear concentration-time courses have to be trans- formed into their equilibrium concentration-response (tar- get or complex) relationships and new structures of drug potency have to be deciphered; when pattern recognition needs to be carried out for an unconventional response- time dataset; when what-if? predictions beyond the obser- vational concentration-time range need to be made; or when the behaviour of a semi-mechanistic model needs to be elucidated or challenged. These four examples are typical situations when standard approaches known to the general community of pharmacokineticists prove to be inadequate. Show less
In this dissertation, we aimed to identify the influence of cortisol exposure and cognitive performance on the clinical course of bipolar disorder. Data regarding sociodemographics, disease... Show moreIn this dissertation, we aimed to identify the influence of cortisol exposure and cognitive performance on the clinical course of bipolar disorder. Data regarding sociodemographics, disease characteristics and genetic analysis of the cortisol receptors, were collected of 366 patients with bipolar disorder (BD). Part of this cohort participated in the longitudinal study, including the Test for Attentional Performance, prospectively registration of mood, and the collection of hair samples to assess long term cortisol. The main findings are as follows: 1) Several Glucocorticoid Receptor (GR) gene polymorphisms, in particular the 9β polymorphism (rs6198), relate with clinical characteristics of BD. The most important relations were with the number of (hypo)manic episodes, and second, with seasonal patterns of mood episodes, especially hypomania. 2) Higher long term cortisol exposure is associated with more psychiatric co morbidity in BD patients., and with an older age at onset, indicating a subgroup of patients. 3) Medication as potential confounder on cognitive performance, appeared to relate with the type (mainly antipsychotics) and the number of different types of medication used. Summarizing, cortisol exposure is associated with several clinically relevant phenomena defining course of BD and give insight in possible subgroups of patients with higher cortisol exposure. Show less
Voorhoeve, P.G.; Mechelen, W. van; Uitterlinden, A.G.; Delemarre-van de Waal, H.A.; Lamberts, S.W.J. 2011
