PhD, Medicinal Chemistry
Racemic (RS)-amisulpride (Solian®) is an atypical antipsychotic drug used to treat schizophrenia and dysthymia. Blockade of dopamine D2/D3 and/or serotonin 5-HT7 receptors is implicated in its pharmacological effects. While the (S)-amisulpride isomer possesses a robust discriminative cue, discriminative stimulus properties of (RS)-amisulpride have not been evaluated.
The present study established (RS)-amisulpride as a discriminative stimulus and assessed amisulpride-like effects of amisulpride stereoisomers, other benzamide derivatives, and antipsychotic, antidepressant, and anxiolytic drugs.
Adult, male C57BL/6 mice were trained to discriminate 10 mg/kg (RS)-amisulpride from vehicle in a two-lever food-reinforced operant conditioning task.
(RS)-Amisulpride’s discriminative stimulus was dose-related, time-dependent, and stereoselective. (S)-Amisulpride (an effective dose of 50% (ED50) = 0.21 mg/kg) was three times more potent than (RS)-amisulpride (ED50 = 0.60 mg/kg) or (R)-amisulpride (ED50 = 0.68 mg/kg). (RS)-Amisulpride generalized fully to the structurally related atypical antipsychotic/antidysthymia drug sulpiride (Sulpor®; ED50 = 7.29 mg/kg) and its (S)-enantiomer (ED50 = 9.12 mg/kg); moderate to high partial generalization [60–75% drug lever responding (%DLR)] occurred to the benzamide analogs tiapride (Tiapridal®) and raclopride, but less than 60% DLR to metoclopramide (Reglan®), nemonapride (Emilace®), and zacopride. Antipsychotic, antidepressant, and antianxiety drugs from other chemical classes (chlorpromazine, quetiapine, risperidone, and mianserin) produced 35–55% amisulpride lever responding. Lastly, less than 35% DLR occurred for clozapine, olanzapine, aripiprazole imipramine, chlordiazepoxide, and bupropion.
(RS)-Amisulpride generalized to some, but not all benzamide derivatives, and it failed to generalize to any other antipsychotic, antidepressant, or antianxiety drugs tested. Interestingly, the (R)-isomer shared very strong stimulus properties with (RS)-amisulpride. This finding was in contrast to findings from Donahue et al. (Eur J Pharmacol 734:15–22, 2014), which found that the (R)-isomer did not share very strong stimulus properties when the (S)-isomer was the training drug.
We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ERα), mimic the ability of BRCA1 to inhibit ERα activity (“BRCA1-mimetics”), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 (“NSC35446.HCl”), also inhibited the growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the downstream effects of NSC35446.HCl and its mechanism of action.view more
Previous studies indicate that BRCA1 protein binds to estrogen receptor-alpha (ER) and inhibits its activity. Here, we found that BRCA1 over-expression not only inhibits ER activity in anti-estrogen-resistant LCC9 cells but also partially restores their sensitivity to Tamoxifen. To simulate the mechanism of BRCA1 inhibition of ER in the setting of Tamoxifen resistance, we created a three-dimensional model of a BRCA1-binding cavity within the ER/Tamoxifen complex; and we screened a pharmacophore database to identify small molecules that could fit into this cavity.view more
Context: Resistance to conventional antiestrogens is a major cause of treatment failure and,
ultimately, death in breast cancer.
Objective: The objective of the study was to identify small-molecule estrogen receptor (ER)-a antagonists
that work differently from tamoxifen and other selective estrogen receptor modulators.
Design: Based on in silico screening of a pharmacophore database using a computed model of the
BRCA1-ER-a complex (with ER-a liganded to 17-estradiol), we identified a candidate group of
small-molecule compounds predicted to bind to a BRCA1-binding interface separate from the
ligand-binding pocket and the coactivator binding site of ER-a. Among 40 candidate compounds,
six inhibited estradiol-stimulated ER-a activity by at least 50% in breast carcinoma cells, with IC50
values ranging between 3 and 50 M. These ER-a inhibitory compounds were further studied by
molecular and cell biological techniques.
Results: The compounds strongly inhibited ER- activity at concentrations that yielded little or no
nonspecific toxicity, but they produced only a modest inhibition of progesterone receptor activity.
Importantly, the compounds blocked proliferation and inhibited ER-a activity about equally well in
antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Representative compounds disrupted
the interaction of BRCA1 and ER-a in the cultured cells and blocked the interaction of ER-a with
the estrogen response element. However, the compounds had no effect on the total cellular ER-a
Conclusions: These findings suggest that we have identified a new class of ER-a antagonists that
work differently from conventional antiestrogens (eg, tamoxifen and fulvestrant).
Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10 mg/kg, s.c.) from vehicle in a two-lever drug discrimination task for food reward. The (S)-amisulpride stimulus was rapidly acquired and was shown to be dose-related, time dependent (effective between 30 and 120 min) and stereoselective: (S)-amisulpride (ED50=1.77 mg/kg; 4.2 µmol/kg) was about three times more potent than rac-amisulpride (ED50=4.94 mg/kg; 13.4 µmol/kg) and ten times more potent than (R)-amisulpride (ED50=15.84 mg/kg; 42.9 µmol/kg). In tests of stimulus generalization, the (S)-amisulpride stimulus generalized completely to sulpiride (ED50=12.67 mg/kg; 37.1 µmol/kg), a benzamide analog that also is purported to be an atypical antipsychotic, but did not fully generalize to the typical antipsychotic drug haloperidol (maximum of 45% drug-lever responding) nor to the atypical antipsychotic drugs clozapine (partial substitution of 65% drug-lever responding) or aripiprazole (~30% drug-lever responding). These results demonstrated that (S)-amisulpride appears to exert a unique discriminative stimulus effect that is similar to other benzamides, but which differs from other structural classes of antipsychotic drugs.view more
The leukotriene A(4) hydrolase enzyme is a dual functioning enzyme with the following two catalytic activities: an epoxide hydrolase function that transforms the lipid metabolite leukotriene A(4) to leukotriene B(4) and an aminopeptidase function that hydrolyzes short peptides. To date, all drug discovery efforts have focused on the epoxide hydrolase activity of the enzyme, because of extensive biological characterization of the pro-inflammatory properties of its metabolite, leukotriene B(4). Herein, we have designed a small molecule, 4-methoxydiphenylmethane, as a pharmacological agent that is bioavailable and augments the aminopeptidase activity of the leukotriene A(4) hydrolase enzyme.view more
Hermitamides A and B are lipopeptides isolated from a Papau New Guinea collection of the marine cyanobacterium Lyngbya majuscula. We hypothesized that the hermitamides are ligands for the human voltage-gated sodium channel (hNa(V)) based on their structural similarity to the jamaicamides. Herein, we describe the nonracemic total synthesis of hermitamides A and B and their epimers. We report the ability of the hermitamides to displace [(3)H]-BTX at 10 μM more potently than phenytoin, a clinically used sodium channel blocker.view more