Interaction of formamidines with octopamine-, dopamine-and 5-hydroxytryptamine-sensitive adenylate cyclase in the nerve cord of Periplaneta americana†

The interaction of chlordimeform, N1-demethylchlordimeform [N2-(4-chloro-o-tolyl)-N1-methylformamidine], BTS-27271 [N1-methyl-N2-(2,4-xylyl)formamidine, the 2,4-xylyl analogue of N1-demethylformamidine], and amitraz with octopamine-, dopamine-, and 5-hydroxytryptamine-mediated enhancement of cyclic-AMP production was investigated in nerve cord homogenates of the American cockroach Periplaneta americana. N1-Demethylchlordimeform, BTS-27271 and amitraz simulated the actions of the monoamines in enhancing cyclic-AMP production, whereas chlordimeform showed no such agonism. Additivity studies indicated that these formamidine derivatives were interacting with dopamine- and 5-hydroxytryptamine-sensitive sites, in addition to their known interaction with octopamine-sensitive adenylate cyclase. N1-Demethylchlordimeform (Ki= 0.2μM) and amitraz (Ki=0.5μM) inhibited the dopamine-mediated response, but only N1-demethylchlordimeform (Ki=2μM) effected appreciable inhibition of the octopamine-response. Pharmacological characterisation of the formamidineinduced elevation of cyclic-AMP production indicated that the agonistic effects of formamidines are expressed primarily through the octopamine-sensitive adenylate cyclase, rather than the dopamine- or 5-hydroxytryptamine-sensitive sites. The results are discussed in the light of the proposal that the behavioural changes, associated with formamidine poisoning, reflect the cumulative effects of octopamine-agonism, and antagonism of the dopamine- and 5-hydroxytryptaminemediated processes.