Pyrazolo[1,5-<i>a</i>]pyrimidines:  Estrogen Receptor Ligands Possessing Estrogen Receptor β Antagonist Activity.

Compton, Dennis R.; Sheng, Shubin; Carlson, Kathryn E.; Rebacz, Natalie A.; Lee, In Young; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

doi:10.1021/jm058162z

Cited by 126 publications

(40 citation statements)

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“…The selectivity of these drugs for one receptor subtype over the other have been previously demonstrated by others (Compton et al 2004;Frasor et al 2003;Harrington et al 2003, Kraichely et al 2000Meyers et al 2001, Stauffer et al 2000Sun et al 2002Sun et al , 2003. The effective doses of PPT, DPN and MPP that significantly modulated PPI or startle in the present study (see Results section), are also known to be equivalent to doses of E2 or estradiol benzoate (EB) previously shown to affect uterine weight or behavioral readouts (Harris et al, 2002;Lynch et al, 2014;Santollo and Eckel, 2009).…”

Section: Drug Preparation and Administrationsupporting

confidence: 82%

“…DPN and PHTPP show a 70--and 36--fold selectivity, respectively, for ER--β over ER--α (Compton et al 2004, Meyers et al 2001). All ER--ligands used in the present study have previously been shown to reach the brain and exert central effects in rodents (Dillon et al, 2013;Grassi et al 2013;Harris et al 2002;Lund et al 2005;Saleh et al, 2013;Santollo and Eckel, 2009;Santollo et al 2007Santollo et al , 2010.…”

Section: Introductionmentioning

confidence: 94%

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Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice

2015

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Rationale. Multiple lines of evidence suggest that the sex steroid hormone 17--β estradiol (E2) plays a protective role in schizophrenia. Systemic E2 enhances prepulse inhibition (PPI) of the acoustic startle reflex, an operational measure of sensorimotor gating known to be impaired in schizophrenia and related disorders. However, the relative contribution of different estrogen--receptor (ER) isoforms in these associations still awaits examination. Results. Acute pharmacological stimulation and blockade of ER--α, respectively, led to a dose--dependent increase and decrease in basal PPI. In contrast, acute treatment with preferential ER--β modulators spared PPI under basal conditions. Pretreatment with either ER--α or ER--β agonist was, however, effective in blocking amphetamine--induced PPI disruption. Conclusions.Our study demonstrates that activation of either ER isoform is capable of modulating dopamine--dependent PPI levels. At the same time, our results suggest that endogenous ER--α signaling may be more relevant than ER--β in the regulation of sensorimotor gating under basal conditions.

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Section: Drug Preparation and Administrationsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 94%

Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice

2015

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“…daily with 2 mg PHTPP (TOCRIS) (12) diluted in ethanol at a final concentration of 100 mM. PHTPP was incubated at 37˚C before further dilution in RPMI 1640.…”

Section: Treatment With Phtpp and Indazole-clmentioning

confidence: 99%

ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity

Aggelakopoulou

Kourepini

Paschalidis

et al. 2016

The Journal of Immunology

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The development of therapies for multiple sclerosis targeting pathogenic T cell responses remains imperative. Previous studies have shown that estrogen receptor (ER) β ligands could inhibit experimental autoimmune encephalomyelitis. However, the effects of ERβ-specific ligands on human or murine pathogenic immune cells, such as Th17, were not investigated. In this article, we show that the synthetic ERβ-specific ligand 4-(2-phenyl-5,7-bis[trifluoromethyl]pyrazolo[1,5-a]pyrimidin-3-yl)phenol (PHTPP) reversed established paralysis and CNS inflammation, characterized by a dramatic suppression of pathogenic Th responses as well as induction of IL-10–producing regulatory CD4+ T cell subsets in vivo. Moreover, administration of PHTPP in symptomatic mice induced regulatory CD4+ T cells that were suppressive in vivo. PHTPP-mediated experimental autoimmune encephalomyelitis amelioration was canceled in mice with ERβ-deficient CD4+ T cells only, indicating that expression of ERβ by these cells is crucial for the observed therapeutic effect. Importantly, synthetic ERβ-specific ligands acting directly on CD4+ T cells suppressed human and mouse Th17 cells, downregulating Th17 cell signature gene expression and expanding IL-10–producing T cells among them. TGF-β1 and aryl hydrocarbon receptor activation enhanced the ERβ ligand-mediated expansion of IL-10–producing T cells among Th17 cells. In addition, these ERβ-specific ligands promoted the induction and maintenance of Foxp3+ T regulatory cells, as well as their in vitro suppressive function. Thus, ERβ-specific ligands targeting pathogenic Th17 cells and inducing functional regulatory cells represent a promising subset of therapeutic agents for multiple sclerosis.

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“…New series of isoxazolines has been synthesized and has shown moderate antimicrobial activity 59 [70]. Pyrimidine analogues: N-fused analogues of chalcones particularly pyrimidines have received augmented interest due to their plethora of biological actions such as antifungal [71], antibacterial [72], antitumor [73], analgesics [74], anti-inflammatory [75], anti-trichomonal [76], KDR kinase inhibition [77], CRF-1 receptor antagonists [78,79] estrogen receptor ligands, and COX-2 selective inhibition [80]. Sharma et al synthesized a series of quinolinyl chalcones and quinolinyl pyrimidines and screened them against M. tuberculosis and NF-54 strains of P. falciparum among all compounds with 4-amino linkage showed promising activity against NF-54 strains of P. falciparum.…”

Section: Analogues Of Chalcones Pyrazoline Analogues With Various Phamentioning

confidence: 99%

Chalconoid Derived Heterocycles as Potent Bioactive Molecules: A Review

Sapra¹,

Sharma²

2016

Chem Sci J

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Although chalcones symbolize an important pharmacophore for variety of biological actions, however their analogues are also reported to be equally important for plethora of biological actions. In the present review, a comprehensive study of chalcones derived molecules (like pyrazoles, isoxazoles, pyridine, pyrimidine) their pharmacological actions, mechanism of action, structure activity relationship studies have been described. which includes anti-proliferative, anti-inflammatory, antioxidant, proapoptotic, anti-bacterial and anti-adhesive effects [18]. Analogues of chalcones Pyrazoline analogues with various pharmacological activities:Pyrazole nucleus present in compounds exhibit wide range of biological activity. Introduction of a pyrazole ring in the chalcones between the two aryl rings increase the cytotoxic activity against a series of human cancer cell lines. Dhar et al. [19] synthesized a series of 1-acetyl-3,5-diaryl-4,5-dihydro-(H)-pyrazoles and assayed for in vitro cytotoxicity against PC-3, OVCAR, IMR-32, HEP-2 human cancer cell lines, compound 1 showed broad spectrum cytotoxic activity against all the four cell lines. The activity shown by the compounds conclude that (i) Substitution on phenyl ring showed marked effect on cytotoxic activity, (ii) Presence of electron donating groups on phenyl ring led to enhanced activity whereas electron withdrawing group except NO 2 reduces the cytotoxic activity, (iii) Replacement of phenyl ring with heterocyclic ring also reduces the cytotoxic potential and napthyl ring on both sides are more beneficial for cytotoxic potential Chemical Sciences JournalChem ic a l S cience s J o u rnal

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Pyrazolo[1,5-a]pyrimidines: Estrogen Receptor Ligands Possessing Estrogen Receptor β Antagonist Activity.

Abstract: The caption of Figure 7 incorrectly suggests that Sprague-Dawley rats were used in studies of HPA activation. Studies of HPA activation were performed using CD-1 mice (as described everywhere else in the manuscript).

Cited by 126 publications

References 0 publications

Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice

Effects of selective estrogen receptor alpha and beta modulators on prepulse inhibition in male mice

ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity

Chalconoid Derived Heterocycles as Potent Bioactive Molecules: A Review

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