Effect of insecticidal cyclic phosphorothionates on adenylate cyclase and phosphodiesterase

Octopamine (0.1 and 1 mM) stimulated the adenylate cyclase prepared from Periplaneta americana ventral nerve cords (615 and 1112% relative to the control). d-(-)-2-Amino-1-phenylethanol (APE) was more potent than 2-amino-1-(4-fluorophenyl)ethanol (an octopamine agonist) and l-(+)-APE in stimulating the adenylate cyclase. 2-Methoxy-5-phenyl-1,3,2,-oxazaphospholidine 2-sulfide (5-PMOS) derived from dl-(±)-APE did not activate adenylate cyclase at 0.75 and 7.5 mM (91 and 95% relative to the control) but suppressed the octopamine (0.1 mM) potency to 268% at 1 mM relative to the control. Salithion (2-methoxy-4H-1,3,2-benzodioxaphosphorin 2-sulfide) at 0.1 mM, fenitrothion (dimethyl 3-methyl-4-nitrophenyl phosphorothionate), 2-amino-1-(2,3-dimethoxy)phenylethanol, 5-PMOS, and other oxazaphospholidines at 1 mM showed similar phenomena. 1-Naphthyl-, 2-naphthyl-, 4-ethylphenyl-, and 4-isopropylphenyloxazaphospholidine derivatives at 0.1 mM reduced the octopamine potency at 0.1 mM more severely than the octopamine-receptor antagonists (chlordimeform and cyproheptadine) at 1 mM. 5-(2,3-Dimethoxyphenyl)-2-methoxy-1,3,2-oxazaphospholidine 2-sulfide (K_i = 107.9 μM), fenitrothion (K_i = 37.3 μM), and 3-isobutyl-1-methylxanthine (K_i = 1.5 μM) reduced the phosphodiesterase activity of beef heart in a competitive manner with respect to cyclic adenosine 3′,5′-monophosphate (cAMP). At 50 μM, salithion, salioxon (2-methoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide), and other oxazaphospholidines reduced phosphodiesterase activity. Hence, d-(-)-APE could be an agonist, and 5-PMOS and salithion analogs and fenitrothion could be partial antagonists to the octopamine receptor. The increased level of whole-body cAMP of Musca domestica and Tribolium castaneum larvae treated with these phosphorothionates is due to reduction of phosphodiesterase activity.