Abstract：
:ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax) are under intensive preclinical and clinical investigation as treatments for hematologic and other malignancies. These small molecules mimic pro-death B-cell lymphoma-2 (Bcl-2) Homology 3 (BH3) domain-only proteins. They also bear a structural resemblance to certain sigma (σ) receptor ligands. Moreover, the Bcl-2 and σ receptor protein families are both located primarily at the endoplasmic reticulum, mediate cell death and survival through protein-protein interactions, and physically associate. Accordingly, we examined the ability of the ABT series of BH3 mimetics to interact with σ receptors using radioligand-binding techniques. Negative allosteric modulation of [3H](+)-pentazocine, an agonist, binding to σ1 receptors in guinea pig brain membranes was observed for ABT-737, ABT-263 and ABT-199. Findings included reduction of specific binding to distinct plateaus in concentration-dependent fashion, significant slowing of radioligand dissociation kinetics, and decreases in radioligand affinity with no or modest changes in maximal receptor densities. Using a ternary complex model, dissociation constants (KX) for modulator binding to the σ1 receptor ranged from 1 to 2.5 μM, while negative cooperativity factors (α), representing the changes in affinity of ligand and modulator when bound as a ternary complex with the receptor, ranged from 0.15 to 0.42. These observations were extended and reinforced by studies using intact small cell (NCI-H69) and non-small cell (NCI-H23) lung cancer cells, and by using an antagonist σ1 receptor radioligand, E-N-1-(3'-[125I]iodoallyl)-N'-4-(3″,4″-dimethoxyphenethyl)piperazine, in mouse brain membranes. By contrast, exploratory studies indicate marked enhancement of the σ2 receptor binding of [3H]1,3-di-(o-tolyl)guanidine/(+)-pentazocine in NCI-H23 cells and guinea pig brain membranes. These findings raise intriguing questions regarding mechanism and potential functional outcomes.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Lever JR,Fergason-Cantrell EAdoi
10.1016/j.phrs.2019.01.040subject
Has Abstractpub_date
2019-04-01 00:00:00pages
87-100eissn
1043-6618issn
1096-1186pii
S1043-6618(18)31579-2journal_volume
142pub_type
杂志文章abstract：:Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that the level of different kinds of matrix metalloproteinases might be downregulated in IPF as it is a matrix degrading collagenase. However, the role of ...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2019.104591
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abstract：:The potential drug-to-drug interaction between darunavir and raltegravir in the setting of HIV infection is a highly debated issue still unresolved. In the present study we have evaluated the pharmacokinetics of darunavir and ritonavir in 53 HIV-1 infected patients with or without concomitant raltegravir administratio...
journal_title：Pharmacological research
pub_type： 临床试验,杂志文章
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abstract：:Several studies on disease and treatment effects on neurohormones have been conducted with small numbers of patients, using one blood sample as representative of their states. The aim of this study was to assess the within-patient variability of plasma concentrations of several hormones and cytokines of recent interes...
journal_title：Pharmacological research
pub_type： 临床试验,杂志文章
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更新日期：1998-03-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章
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journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2017.10.001
更新日期：2018-02-01 00:00:00
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journal_title：Pharmacological research
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pub_type： 杂志文章,评审
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journal_title：Pharmacological research
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doi：10.1016/j.phrs.2003.10.012
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journal_title：Pharmacological research
pub_type： 杂志文章
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更新日期：1992-05-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章,评审
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更新日期：2017-05-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2000.0683
更新日期：2000-09-01 00:00:00
abstract：BACKGROUND AND OBJECTIVES:Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) w...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2011.04.006
更新日期：2011-09-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2016.04.010
更新日期：2016-06-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2000.0702
更新日期：2000-10-01 00:00:00
abstract：:The pharmacological profile of PF-00885706, a selective 5-HT(4) receptor partial agonist, was investigated. PF-00885706 displayed a high binding affinity for the human 5-HT(4d) receptor with a K(i) of 3.7 nM that translates to functional agonist activity in vitro with EC(50) values of 4.0 nM and 6.6 nM in cell-based a...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2009.03.013
更新日期：2009-10-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2017.02.003
更新日期：2017-05-01 00:00:00
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journal_title：Pharmacological research
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更新日期：2021-01-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2017.07.015
更新日期：2017-10-01 00:00:00
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更新日期：2020-05-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2019.104512
更新日期：2020-01-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/s1043-6618(03)00193-2
更新日期：2003-11-01 00:00:00
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journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2004.05.005
更新日期：2005-01-01 00:00:00
abstract：:Injury to the bronchial epithelium in respiratory diseases such as asthma and COPD results in the loss of barrier function and an elevated sensitivity to environmental insults. An increased release of the endogenous cannabinoid, anandamide in response to inhalation of allergen in asthmatic patients has been reported. ...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2016.01.023
更新日期：2016-03-01 00:00:00
abstract：:Cardiac intracellular Na+and Ca2+homeostasis is regulated by the concerted action of ion channels, pumps and exchangers. The Na+, K+-ATPase produces the electrochemical concentration gradient for Na+, which is the driving force for Ca2+removal from the cytosol via the Na+/Ca2+exchange. Reduction of this gradient by in...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1006/phrs.1998.0416
更新日期：1999-03-01 00:00:00
abstract：:The perioperative period is supposed to be a vulnerable period for cancer progression. Results of clinical studies indicate that the use of regional anesthesia can influence and improve oncological outcome of cancer patients. Uncontrolled cell proliferation and resistance to apoptotic cell death are important characte...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2015.03.017
更新日期：2015-05-01 00:00:00
abstract：:Many data suggest an involvement of toxic oxygen radicals in the termination of endurance to muscle fatigue. Being reduced glutathione (GSH), an efficient intracellular physiological antioxidant, experiments have been performed to discover whether exogenous GSH modifies endurance to exhaustive swimming in mice. GSH wa...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/s1043-6618(05)80116-1
更新日期：1991-02-01 00:00:00
abstract：:Mild cognitive impairment (MCI), regarded as the prodromal stage before the clinical phase of Alzheimer's disease (AD), has been considered for early intervention. Unfortunately, many trials in this stage with drugs with single-target turned out to be little or no effect. Multi-targeting in nature based on the theory ...
journal_title：Pharmacological research
pub_type： 临床试验,杂志文章
doi：10.1016/j.phrs.2019.104319
更新日期：2019-08-01 00:00:00
