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A qualitative assessment of developmental toxicity within a series of structurally related dopamine mimetics
1SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.
Abstract:
A qualitative assessment of developmental toxicity within a series of 12 structurally related compounds, 11 of which were active dopamine mimetics and one was inactive, was conducted in rats treated orally by gavage during the major period of organogenesis. Doses were chosen where possible to be equipotent in terms of pharmacological activity. The series was typified by the compound BRL 16644 (2-[[3,4-dihydro-2,2-dimethyl-4-[3-(trifluoromethyl)phenyl]- 2H-1-benzopyran-7-yl]oxy]-N,N-dimethyl-ethanamine: Chemical Abstracts No. 59257-24-8). Five of these compounds were clearly teratogenic producing specific abnormalities typified by anasarca, brachygnathia and cleft palate. Similar levels of maternal toxicity, particularly stereotypic behaviour, and foetotoxicity were seen in both teratogenic and non-teratogenic compounds suggesting that neither maternal nor foetotoxicity plays a role in the aetiology of the abnormalities. Four of the teratogenic compounds contained a trifluoromethyl group in the 4-phenyl ring and, within this series of compounds, substitution with this group appears to confer teratogenicity. Although equipotent doses were used this only pertained to the adult and as only limited pharmacokinetic data were available, including the extent of placental transfer, the influence of this group is not clear. Investigations have been undertaken to relate the teratogenic potential of these compounds to a number of their chemical descriptors, including electronic, steric, quantum chemical and hydrophobicity parameters, to try and clarify the influence of the trifluoromethyl group.
Insights
A study on 12 dopamine-mimetic compounds found five were teratogenic in rats. The trifluoromethyl group in the 4-phenyl ring appears to confer teratogenicity, though its exact influence requires further investigation.
Area of Science:
- Pharmacology
- Toxicology
- Medicinal Chemistry
Background:
- Developmental toxicity is a critical concern for pharmaceutical safety.
- Dopamine mimetics are a class of drugs with potential therapeutic applications but also risks.
- Understanding structure-activity relationships is key to predicting and mitigating teratogenic effects.
Purpose of the Study:
- To qualitatively assess developmental toxicity in a series of structurally related dopamine mimetics.
- To identify structural features associated with teratogenicity.
- To investigate the role of the trifluoromethyl group in conferring teratogenic potential.
Main Methods:
- Oral gavage administration of 12 compounds to rats during organogenesis.
- Doses selected for equipotency based on adult pharmacological activity.
- Qualitative assessment of teratogenic abnormalities, maternal toxicity, and foetotoxicity.
- Analysis of chemical descriptors to correlate with teratogenic potential.
Main Results:
- Five of the 12 compounds were clearly teratogenic, causing abnormalities like anasarca, brachygnathia, and cleft palate.
- Maternal and foetotoxicity levels were similar in both teratogenic and non-teratogenic groups, suggesting they are not primary causes.
- Four teratogenic compounds possessed a trifluoromethyl group in the 4-phenyl ring, indicating this substitution may confer teratogenicity.
- The influence of the trifluoromethyl group remains unclear due to limited pharmacokinetic and placental transfer data.
Conclusions:
- The trifluoromethyl group in the 4-phenyl ring appears to be a key structural determinant for teratogenicity within this series of dopamine mimetics.
- Developmental toxicity is not solely explained by maternal or foetal toxicity.
- Further research is needed to elucidate the precise mechanisms and pharmacokinetic factors underlying the teratogenic effects of these compounds.