TTNPB

TTNPB is a highly potent RAR agonist. Competitive binding assays using human RARs yield IC50s of α=5.1 nM, β= 4.5 nM, and γ=9.3 nM, respectively.

Signaling Pathways >> Metabolic Enzyme/Protease >> RAR/RXR

Research Areas >> Cancer

IC50: 5.1 nM (RARα), 4.5 nM (RARβ), 9.3 nM (RARγ)[1]

TTNPB inhibits binding of [3H]tRA with IC50s of 3.8 nM, 4 nM, and 4.5 nM for human RARα, β, and γ, respectively. TTNPB competes for [3H]tRA binding to CRABPI with IC50s of 1800 nM[1].

Labeled and unlabeled retinoids are added to nucleosol or cytosolic fractions in ethanol so that the total amount of ethanol added is constant in all tubes and did not exceed 2% of the incubation volume. The receptor preparations are incubated with retinoids at 47°C for 4-6 hr. Sephadex PD-10 desalting columns are used to separate bound radioligand from free radioligand after equilibrium is achieved. For competitive binding assays, varying concentrations of unlabeled competing ligand are incubated with the appropriate nucleosol or cytosol in the presence of a fixed concentration of [3H]tRA (sp act. 49.3 Ci/mmol) or [3H]9-cis RA (sp. act. 24.0 Ci/mmol). Final concentrations of [3H] tRA and [3H]9-cis RA for nuclear receptor binding assays are 5nM. Final concentrations of [3H]tRA for CRABP binding assays is 30 nM. The IC50s are calculated. For saturation kinetics, increasing concentrations of radiolabeled ligand ([3H]tRA sp. act. 49.3 Ci/mmol, [3H]TTNPB sp. act. 5.5 Ci/mmol) are added to the nucleosol of the appropriate receptor subtype in the presence (nonspecific binding) or absence (total binding) of a 100-fold molar excess of the corresponding unlabeled retinoid. Specific binding is defined as the total binding minus nonspecific binding. Saturation kinetics are calculated[1].

[1]. Pignatello MA, et al. Multiple factors contribute to the toxicity of the aromatic retinoid, TTNPB (Ro 13-7410): binding affinities and disposition. Toxicol Appl Pharmacol. 1997 Feb;142(2):319-27.

Retinoic acid | AM580 | Tamibarotene | Palovarotene | Fenretinide | Magnolol | AGN 194310 | AGN 193109 | CD437 | Adapalene | AR-7 | Tazarotene | UVI 3003 | Tarenflurbil | AGN 195183

MOLECULAR FORMULA :

C24-H28-O2

MOLECULAR WEIGHT :

348.52

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1040 ug/kg/4D-I

TOXIC EFFECTS :

Skin and Appendages - dermatitis, other (after systemic exposure) Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

TXAPA9 Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- Volume(issue)/page/year: 138,169,1996

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1250 ug/kg/25D-I

TOXIC EFFECTS :

Musculoskeletal - other changes Nutritional and Gross Metabolic - weight loss or decreased weight gain Related to Chronic Data - death

REFERENCE :

JMCMAR Journal of Medicinal Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB POB 57136, West End Stn., Washington, DC 20037) V.6- 1963- Volume(issue)/page/year: 40,3567,1997

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

125 ug/kg/5D-I

TOXIC EFFECTS :

Endocrine - changes in spleen weight Skin and Appendages - dermatitis, other (after systemic exposure) Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

TXAPA9 Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- Volume(issue)/page/year: 138,169,1996

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Implant

SPECIES OBSERVED :

Rodent - guinea pig

DOSE/DURATION :

392 ug/kg/14D-I

TOXIC EFFECTS :

Musculoskeletal - other changes Nutritional and Gross Metabolic - weight loss or decreased weight gain Related to Chronic Data - death

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 34,91,1996 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

30 ug/kg

SEX/DURATION :

female 9 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

REFERENCE :

ARTODN Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- Volume(issue)/page/year: 64,43,1990

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

100 ug/kg

SEX/DURATION :

female 9 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue)

REFERENCE :

ARTODN Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- Volume(issue)/page/year: 64,43,1990

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

37 ug/kg

SEX/DURATION :

female 8 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - eye/ear Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

REFERENCE :

JJIND8 JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. Volume(issue)/page/year: 78,533,1987

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

75 ug/kg

SEX/DURATION :

female 8 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - Central Nervous System

REFERENCE :

JJIND8 JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. Volume(issue)/page/year: 78,533,1987

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

290 ug/kg

SEX/DURATION :

female 8 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

REFERENCE :

JJIND8 JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. Volume(issue)/page/year: 78,533,1987