Evaluation of the genotoxic potential of three phenyltetrahydropyridinyl butylazole-derived sigma-receptor ligand drug candidates.
Three structurally related phenyltetrahydropyridinyl butylazole (PTHPB)-derived drug candidates with sigma receptor-binding properties were evaluated for genotoxic potential in the ICH standard battery of genetic toxicology assays. These comprised an Ames test, a mouse-lymphoma assay, and a mouse bone-marrow micronucleus test. The maximum test concentrations in the in vitro assays were determined by the solubility and/or the cytotoxicity of the compounds. In the mouse micronucleus assay, the compounds were administered orally at three levels up to the maximum tolerated dose (MTD). Negative results were obtained for all three drug candidates in the Ames test and in the mouse-lymphoma assay, both in the absence or presence of metabolic activation. In the mouse micronucleus test, there was no effect on the frequency of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow after oral administration of any of the three test compounds, at any dose level or sampling time (24 and 48h). Administration of all three compounds at the MTD induced a clear decrease in mouse body-temperature of 3.1-4.8 degrees C below normal; the temperature returned to normal within 8h of dose administration. The produced mild hypothermia and absence of micronucleus induction was in contrast to the induction of MNPCE secondary to marked hypothermia reported for a structurally similar PTHPB-derived sigma-receptor ligand, the antipsychotic compound E-5842. The results obtained in the current series of studies suggest that exposure to the three tested PTHPB-derived drug candidates would not pose a genotoxic risk under clinical conditions.
Guzmán
Antonio
A
Toxicology Department, ESTEVE, Mare de Deu de Montserrat 221, 08041 Barcelona, Spain. aguzman@esteve.es
García
Concepción
C
Marín
Ana-Paz
AP
Proudlock
Raymond J
RJ
Fernández de Henestrosa
Antonio R
AR
Ruiz
Maria Teresa
MT
Tortajada
Araceli
A
Lloyd
Mel
M
Marcos
Ricard
R
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000378:metabolism*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004900:Erythroblasts / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008223:Lymphoma / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D015162:Micronucleus Tests / Q000379:methods; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists*; D013997:Time Factors; D014230:Triazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology
D014150:Antipsychotic Agents; C117757:E 5842; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D011084:Polycyclic Aromatic Hydrocarbons; D011725:Pyridines; D017480:Receptors, sigma; D014230:Triazoles