The majority of antidepressants in current use selectively inhibit the reuptake of serotonin and/or norepinephrine. “Broad spectrum” antidepressants are compounds that inhibit the reuptake of ...norepinephrine, serotonin and dopamine, the three biogenic amines most closely linked to depression. The pharmacological profile of one such compound has recently been described (European Journal of Pharmacology, 461 (2003) 99). DOV 21,947, an azabicyclo3.1.0hexane, potently inhibits norepinephrine, serotonin and dopamine reuptake by the corresponding human transporter proteins. DOV 21,947 is orally active in the forced swim and tail suspension tests, preclinical procedures that are highly predictive of antidepressant action in patients. A closely related compound, DOV 216,303 is safe and well-tolerated in Phase I studies. The plasma concentrations of DOV 216,303 following both single and multiple doses appear sufficient to inhibit norepinephrine, serotonin, and dopamine reuptake. Based on the pivotal role proposed for dopamine in depression, it has been hypothesized that a broad spectrum antidepressant will produce a more rapid onset and/or higher efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine.
Bicifadine (1-p-tolyl-3-azabicyclo3.1.0hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine > serotonin > dopamine ...(approximately 1:2:17). This in vitro profile is supported by microdialysis studies in freely moving rats, where bicifadine (20 mg/kg i.p.) increased extrasynaptic norepinephrine and serotonin levels in the prefrontal cortex, norepinephrine levels in the locus coeruleus, and dopamine levels in the striatum. Orally administered bicifadine is an effective antinociceptive in several models of acute, persistent, and chronic pain. Bicifadine potently suppressed pain responses in both the Randall-Selitto and kaolin models of acute inflammatory pain and in the phenyl-p-quinone-induced and colonic distension models of persistent visceral pain. Unlike many transport inhibitors, bicifadine was potent and completely efficacious in both phases of the formalin test in both rats and mice. Bicifadine also normalized the nociceptive threshold in the complete Freund's adjuvant model of persistent inflammatory pain and suppressed mechanical and thermal hyperalgesia and mechanical allodynia in the spinal nerve ligation model of chronic neuropathic pain. Mechanical hyperalgesia was also reduced by bicifadine in the streptozotocin model of neuropathic pain. Administration of the D(2) receptor antagonist (-)-sulpiride reduced the effects of bicifadine in the mechanical hyperalgesia assessment in rats with spinal nerve ligations. These results indicate that bicifadine is a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models, with activation of dopaminergic pathways contributing to its antihyperalgesic actions.
DOV 21,947 (+)-1-(3,4-dichlorophenyl)-3-azabicyclo-3.1.0hexane hydrochloride inhibits the reuptake of
3Hserotonin,
3Hnorepinephrine, and
3Hdopamine in human embryonic kidney (HEK) 293 cells ...expressing the corresponding human recombinant transporters (IC
50 values of 12, 23, and 96 nM, respectively). This compound also inhibits
125IRTI 55 (3β-(4-iodophenyl)tropane-2β-carboxylic acid methyl ester) binding to the corresponding transporter proteins in membranes prepared from these cells (
K
i values of 99, 262, and 213 nM, respectively). DOV 21,947 reduces the duration of immobility in the forced swim test (using rats) with an oral minimum effective dose of 5 mg/kg. This antidepressant-like effect manifests in the absence of significant increases in motor activity at doses of up to 20 mg/kg. DOV 21,947 also produces a dose-dependent reduction in immobility in the tail suspension test, with a minimum effective oral dose of 5 mg/kg. The ability of DOV 21,947 to inhibit the reuptake of three biogenic amines closely linked to the etiology of depression may result in a therapeutic profile different from antidepressants that inhibit the reuptake of serotonin and/or norepinephrine.
The National Institute of Standards and Technology administers quality assurance programs devoted to improving measurements of nutrients and related metabolites in foods, dietary supplements, and ...serum and plasma samples. These programs have been developed in collaboration with the National Institutes of Health to assist measurement communities in their efforts to achieve accurate results that are comparable among different laboratories and over time. Targeted analytes include micronutrients, botanical markers, nutritional elements, contaminants, fatty acids, and vitamin D metabolites.
Covalently modified surfaces represent a unique state of matter that is not well described by liquid or solid phase models. The chemical bond in tethered alkanes imparts order to the surface in the ...form of anisotropic properties that are evident in chromatographic and spectroscopic studies. An understanding of the structure, conformation, and organization of alkyl-modified surfaces is requisite to the design of improved materials and the optimal utilization of existing materials. In recent years, the study of alkyl-modified surfaces has benefited from advances in modern analytical instrumentation. Aspects of alkyl chain conformation and motion have been investigated through the use of nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, fluorescence spectroscopy, and neutron scattering studies. Chromatography provides complementary evidence of alkyl chain organization through interactions with solute probes. Computational simulations offer insights into the structure of covalently modified surfaces that may not be apparent through empirical observation. This manuscript reviews progress achieved in the study of the architecture of alkyl-modified surfaces.
Anxioselective anxiolytics: can less be more? Basile, Anthony S.; Lippa, Arnold S.; Skolnick, Phil
European journal of pharmacology,
10/2004, Letnik:
500, Številka:
1
Journal Article
Recenzirano
Benzodiazepines remain widely used for the treatment of anxiety disorders despite a side-effect profile that includes sedation, myorelaxation, amnesia, and ataxia, and the potential for abuse. ...γ-Aminobutyric acid
A (GABA
A) receptor partial agonists, subtype-selective agents, and compounds combining both of these features are being developed in an attempt to achieve benzodiazepine-like efficacy without these potentially limiting side effects. This article reviews the nonclinical and clinical studies of “anxioselective” anxiolytics that target GABA
A receptors and discusses potential mechanisms subserving an anxioselective profile.
Abstract
Background
Integrin α4β7 regulates the recruitment of T cells to intestinal mucosa through its interaction with mucosal addressin cell adhesion molecule (MAdCAM)-1. Disruption of this ...interaction has been clinically validated for the treatment of inflammatory bowel diseases (IBD) by the anti-α4β7 antibody vedolizumab. The current study was aimed at elucidating the preclinical efficacy of MT-103, a potent and selective small molecule α4β7 inhibitor in the clinically relevant CD4+CD45RBhi T cell transfer (TCT) colitis mouse model.
Methods
Mice were administered either MT-103 via subcutaneously implanted minipumps across 3 dose cohorts (3, 10, or 30 mg/ml), or an antibody specific for IL12p40 (25 mg/kg) or α4β7 (30 mg/kg), through intraperitoneal injections for 7 weeks. Colitis development was evaluated via readouts including body weights, gross colon weight by length ratios, colonic tissue gene expression, and histopathological scores.
Results
MT-103 significantly inhibited the development of colitis in mice at all 3 doses equivalently, as evident from significantly improved gross colon weight/length ratios in comparison to vehicle controls which presented with moderate-severe colitis (Figure 1A). MT-103 treatment also led to a significant protection from weight loss that occurred in vehicle-treated mice. Importantly, mice treated with MT-103 exhibited remarkably improved histopathology scores, including inflammation, hyperplasia, and gland loss compared to vehicle controls (Figure 1B). Furthermore, broad gene transcriptional analysis showed that MT-103 broadly suppressed pro-inflammatory pathways and processes within colonic tissues. Specifically, MT-103-induced downregulation of Ifng, Il17a, and Il1b, besides reduced Cd3 as a surrogate metric of T cell trafficking inhibition to the colon, and conversely enabled upregulation of anti-inflammatory cytokine Il10. The colitis-protective effects of MT-103 were equivalent, if not superior, to the saturating doses of α4β7 mAb or anti-IL12p40 mAb when compared to their respective vehicle controls.
Conclusion
Treatment with MT-103 protects from colitis by restoring colonic tissue homeostasis as measured by body fitness and an array of immunological and histopathological assessments. These proof-of-concept data demonstrate an α4β7-specific small molecule, MT-103, can occlude pathogenic T cells from initiating disease in a chronic IBD model, equivalent to an α4β7 blocking antibody.
Abstract
Background
MORF-057 is a potent and selective small molecule inhibitor of the α 4β 7 integrin. Using a receptor occupancy (RO) assay under physiologically relevant conditions, MORF-057 ...achieves 90% α 4β 7 RO at approximately 10 nM in human whole blood. The current studies evaluate nonclinical pharmacokinetics (PK) and properties of absorption, distribution, metabolism, and excretion (ADME) to enable dose/exposure projection to humans.
Methods
PK studies were conducted in mouse, rat, dog, and monkey following intravenous (IV) and oral administration. ADME studies were conducted in vitro and in rats using carbon-14 14C labeled MORF-057. MORF-057 levels were quantified using liquid chromatography coupled with tandem mass spectrometry. Human PK was predicted based on body weight allometry, well-stirred and semi-physiological models.
Results
MORF-057 exhibited low to moderate clearance (CL) in animals with species dependent volume of distribution (Vdss) resulting in half-lives of 1.1 to 2.7 hours (Table 1). Following an oral dose, absorption was high with bioavailability ranging from 15% to 49%. MORF-057 is highly protein bound and distribution of 14CMORF-057 derived radioactivity in rat was predominantly in the small intestine wall, liver, and stomach wall. Rifampin, an inhibitor of organic anion transporting polypeptides, decreased MORF-057 clearance by 3-fold in monkeys suggesting MORF-057 elimination involves hepatic uptake transport. MORF-057 is further cleared via CYP3A metabolism followed by biliary/fecal elimination of metabolites. MORF-057 is predicted to have moderate bioavailability (40%) and CL (6.5 mL/min/kg) in humans. Wajima transformation shows good agreement of the normalized PK across animal species, with a predicted human concentration-time profile supporting >90% α 4β 7 RO at trough following 200 mg twice daily dose (Figure 1).
Conclusion
These data demonstrate that MORF-057 is well absorbed and PK properties in animals support the potential for achieving high α4β7 RO following oral administration in humans. These nonclinical results provided a basis for the progression of MORF-057 into a first-in-human Phase 1 clinical study assessing safety, pharmacokinetics, and receptor occupancy (results being reported separately).
Abstract
Background
Disruption of immune cell trafficking via integrins is a proven and effective mechanism for treating inflammatory bowel disease. When α4β7 integrin is inhibited through ...pharmacological intervention, immune cells destined for the gut tissue become sequestered in blood circulation and these alterations can be detected through several methods. MORF-057 is a novel, oral, selective, small molecule inhibitor of α4β7 integrin developed for treating IBD. MORF-057 demonstrated favorable tolerability, pharmacokinetic and pharmacodynamic profiles including saturating receptor occupancy and corresponding evidence for proof of biology based on effects on circulating cells during a Phase 1 clinical trial in healthy volunteers (Ray, ECCO 2021). Here we demonstrate an exposure:response relationship of α4β7 related biomarkers examined among MORF-057 treated non-human primates (NHPs) as a means for pre-clinical testing of inhibitors of this pathway.
Methods
Single-cell RNA sequencing (scRNAseq) was performed on NHP CD45+ blood cells to determine baseline populations potentially impacted through exposure to MORF-057. 40 Naïve cynomolgus monkeys were enrolled over 5 separate studies and dosed orally BID with MORF-057 over 2–7 days using several dose levels to examine biomarker dynamics over a wide range of exposures. Peripheral blood was sampled at various timepoints (n= 125) and assayed using: mass spectroscopy, flow cytometry (FACS), and mRNA quantification to determine MORF-057 exposure levels, on-target receptor occupancy (RO), immune cell subset changes, and CCR9 mRNA levels.
Results
MORF-057 Ctrough ranged from 3.3–429 ng/ml. In samples tested for RO, MORF-057 achieved >95% saturation of α4β7 even with the lowest Ctrough of 4.5 ng/ml. MORF-057 treatment led to significantly sustained increases in circulating β7high CD4+ T memory cells detectable as early as 24h post-exposure. A maximal effect where β7high cells accounted for approximately 60% of the T memory population was achieved at saturating receptor occupancy (Fig., left). CCR9 mRNA values demonstrated increases upon drug exposure (Fig., right).
Conclusion
In NHP, acute changes in circulating β7high T memory cells was a sensitive biomarker demonstrating a dose-dependent response to MORF-057 exposure. CCR9 mRNA levels also showed similar exposure related changes reflecting its expression on a subset of β7high cell types. Analysis of scRNAseq shows expression of α4β7 on other cell types beyond T memory cells including: NK, NKT, B cells, plasmablasts, monocytes, and eosinophils. Pharmacodynamic changes in NHP are consistent with human Phase 1 data in healthy volunteers.
In Alzheimer's disease brains, more than 90% of pyramidal neurons in lamina V and 70% in lamina III displayed 2- to 5-fold elevated levels of cathepsin D (Cat D) mRNA by in situ hybridization ...compared with neurologically normal controls. Most of these cells appeared histologically normal. The less vulnerable nonpyramidal neuron population in lamina IV had relatively normal message levels. Neuronal populations expressing more Cat D mRNA also displayed quantitatively increased Cat D immunoreactive protein. Cat D mRNA expression was only moderately increased in astrocytes. Degenerating neurons exhibited intense immunoreactivity but lowered Cat D mRNA levels. The upregulation of Cat D synthesis and accumulation of hydrolase-laden lysosomes indicate an early activation of the endosomal-lysosomal system in vulnerable neuronal populations, possibly reflecting early regenerative or repair processes. These abnormalities also represent a basis for altered regulation of amyloid precursor protein processing.
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