Barbara Bricker

Florida A&M University, Tallahassee, Florida, United States

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Publications (7)16.44 Total impact

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    ABSTRACT: Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP(+)-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP(+)) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.
    Bioorganic & medicinal chemistry letters. 07/2014;
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    ABSTRACT: The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4=0.84nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4=3.9nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100nM (Ki <100nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.
    Bioorganic & medicinal chemistry 04/2014; · 2.82 Impact Factor
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    ABSTRACT: Haloperidol induced catalepsy was determined using the classic bar test and a new MED Associates Catalepsy Test Chamber instrument. The dose that produced an adverse effect in 50% of rats (AED50) for haloperidol was calculated using the instrument data as 0.29 mg/kg. Hand scoring of the video recordings gave AED50 values of 0.30 and 0.31 mg/kg, both well within the 95% CL of the instrument data. Clozapine was also evaluated and catalepsy was not detected up to 40 mg/kg. No significant difference was found between the instrument and hand scoring data. The instrument was useful for testing haloperidol and clozapine, relieving much of the tedium and variability experienced without its use. It was especially valuable at measuring shorter time periods, where the researcher cannot react as quickly. Finally, olanzapine was also evaluated. However, clenched forepaws and hind paws prevented the use of the instrument alone at higher doses. A backup stopwatch was used for the bar test in these cases. Some of the advantages and limitations are discussed. Results are also compared to the crossed-legs position (CLP) test for all three antipsychotics. While haloperidol gave similar results at all concentrations tested, clozapine deviated significantly at the highest dose (40 mg/kg) displaying catalepsy in the CLP test but not in the bar test. Olanzapine displayed catalepsy in rats significantly different from vehicle at 40 mg/kg in both the bar and CLP tests. However, the CLP test may be more suited to compounds with gripping problems which prevent the consistent grasping of the bar. Overall, the instrument was found to be a useful aid in conducting the bar test for catalepsy. The CLP test was found to complement the bar test under certain conditions and could provide additional data that might be missed by the bar test for compounds producing grasping problems.
    Pharmacology Biochemistry and Behavior 01/2014; · 2.82 Impact Factor
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    ABSTRACT: SYA013, a homopiperazine analog of haloperidol, was further evaluated for antipsychotic potential using additional animal models. Previously, SYA013 was tested in mice with an antipsychotic screening model in which it inhibited apomorphine induced climbing behavior, indicating antagonism of the dopaminergic system and the potential for use in the treatment of schizophrenia. In this study, SYA013 was shown to inhibit both d-amphetamine-induced locomotor activity in rats and conditioned avoidance response (CAR) in rats in a dose dependent manner and in the case of CAR, without producing any escape failure responses (EFRs), two tests predictive of antipsychotic action. The selective 5HT(1A) antagonist WAY100,635 was used to determine if binding of SYA013 to the 5HT(1A) receptor contributed to suppression of CAR. The results indicated that 0.63mg/kg WAY100,635 did not have a significant effect on the inhibition of CAR by SYA013. Pharmacokinetic parameters in brain and plasma were determined for SYA013. A log brain/plasma concentration ratio at a t(max) of 1.48 suggests that SYA013 readily crosses the blood brain barrier (BBB). The hypothesis that binding of SYA013 to the 5HT(1A) receptor contributed to the lack of significant catalepsy was investigated using the 5HT(1A) antagonist WAY100,635. The results of acute and semi-chronic tests suggest that binding to the 5HT(1A) receptor alone did not significantly account for the lack of catalepsy. Lack of catalepsy was preserved after the semi-chronic challenge with SYA013. These tests further indicate that SYA013 has a pharmacological profile with the potential for use in the treatment of neuropsychiatric diseases. In addition, the 5HT(1A) receptor does not appear to play a significant role in the pharmacological profile of SYA013.
    Pharmacology Biochemistry and Behavior 05/2012; 102(2):294-301. · 2.82 Impact Factor
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    ABSTRACT: Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis, respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf. 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.
    Bioorganic & medicinal chemistry 01/2011; 19(1):458-70. · 2.82 Impact Factor
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    ABSTRACT: The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
    Bioorganic & medicinal chemistry 07/2008; 16(15):7291-301. · 2.82 Impact Factor
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    ABSTRACT: Enantiomeric separation of the racemic 4-{3-(4-chlorophenyl)-3-hydroxypyrrolidin-1-yl}-1-(4-fluorophenyl)butan-1-one, a pyrrolidine analog of haloperidol, {(+/-)-SYA 09}, and subsequent binding studies revealed that most of the binding affinity at dopamine and serotonin receptors resides in the (+)-isomer {(+)-SYA 09} or the eutomer. Further pharmacological evaluation of the eutomer revealed that it has a higher affinity for the dopamine D4 (DAD4) receptor subtype (Ki = 3.6 nM) than for the DAD2 subtype (Ki = 51.1 nM) with a ratio of 14.2 (D2Ki/D4Ki ratio = 14.2). In an animal model of antipsychotic efficacy, the (+)-SYA 09 was efficacious with an ED50 value of 1.6 mg/kg, i.p., and at twice this value, (+)-SYA 09 did not induce significant catalepsy in rats.
    Bioorganic & Medicinal Chemistry Letters 07/2006; 16(12):3219-23. · 2.34 Impact Factor

Publication Stats

30 Citations
16.44 Total Impact Points

Institutions

  • 2011–2014
    • Florida A&M University
      • • Division of Basic and Pharmaceutical Sciences
      • • College of Pharmacy and Pharmaceutical Sciences
      Tallahassee, Florida, United States