Interaction of the pesticide chlordimeform with adrenergic receptors in mouse brain: an in vitro study

Chlordimeform (N'(4-chloro-o-tolyl)-N, N-dimethylformamidine; CDM) is a formamidine insecticide/acaricide whose major active metabolite is its N-monomethyl analog, desmethylchlordimeform, (DCDM). While their pesticidal action in invertebrates appears to be related to activation of octopamine receptors, their mechanism of action in mammals has not been established. Because of similarities between octopamine and adrenergic receptors and suggestions of CDM and DCDM action on adrenoceptors, the in vitro interactions of CDM and DCDM with adrenoceptors were studied. In mouse brain membrane preparations CDM inhibited the binding of ³H]-clonidine to alpha₂- adrenoceptors and of ³H]-WB4101 to alpha₁-adrenoceptors with IC₅₀ values of 18.2 and 87 M, respectively. DCDM was a much more potent inhibitor, with IC₅₀ values toward alpha_2–, and alpha₁-adrenoceptors of 44 nM and 1 M, respectively. Both compounds were only weak inhibitors of the binding of ³H]-dihydroalprenolol to beta-adrenoceptors and of ³H]-quinuclidinyl benzilate to muscarinic receptors and were inactive toward benzodiazepines and gamma aminobutyric acid (GABA_A) receptors. Inhibition of ³H]-clonidine binding by both compounds was competitive, as indicated by a decreased receptor affinity without changes in receptor density. Interaction of CDM and DCDM with ³H]-WB4101 binding, on the other hand, was more complex, and not of the competitive type. These results show that CDM and its metabolite DCDM can interact directly in vitro with alpha-adrenergic receptors, suggesting that these receptors could mediate some of the effects of CDM and DCDM in vivo.