NORCHLORCYCLIZINE ANALOGS: RELATIONSHIP OF TERATOGENIC ACTIVITY TO IN VITRO CARTILAGE BINDING

¹ Pharmacology Section, Laboratory of Biochemistry, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland

Structural analogs of norchlorcyclizine were tested for teratogenic activity by direct intrauterine application over 13-day rat embryos and for in vitro cartilage binding affinity by the addition of these compounds to suspensions of bovine nasal septum. The following compounds induce both cleft palate and malformations of the left forelimb: norchlorcyclizine and norhomochlorcyclizine (30%); normethylcyclizine, homochlorcyclizine and norcyclizine (10%); chlorcyclizine, methylcydlizine, chlorcyclizine-N-tert.-butyl and cyclizine (<5%). Chlorcyclizine-N-oxide, chlorbenzylpiperazine, chlorbenzhydrol and piperazine do not produce malformations. Most of these same nitrogen compounds are capable of binding to cartilage, although their binding strengths vary according to cation concentration. Thus, when Ca⁺⁺ is excluded from the reaction, the amines are bound at about 1.0 mEq of N⁺ per g of cartilage; however, when 0.25 mg Ca⁺⁺ is added with 5 mg of norchlorcyclizine, chlorcyclizine or chlorbenzylpiperazine, the amines are bound at 0.85,0.60 and 0 mEq of N⁺ per g. When 1.0 mg Ca⁺⁺ is added, these amines are bound at 0.31,0.11 and 0 mEq of N⁺ per g. These results demonstrate a parallel between the compound's teratogenic activity and its relative ability to bind with cartilage.