Ophiobolin M and analogues, noncompetitive inhibitors of ivermectin binding with nematocidal activity.

A series of ophiobolins were isolated from a fungal extract based on their nematocidal activity. These compounds are non-competitive inhibitors of ivermectin binding to membranes prepared from the free-living nematode, Caenorhabditis elegans, with an inhibition constant of 15 microM. The ophiobolins which were most potent in the biological assays, ophiobolin C and ophiobolin M, were also the most potent compounds when evaluated in a C. elegans motility assay. These data suggest that the nematocidal activity of the ophiobolins is mediated via an interaction with the ivermectin binding site. The isolation, structure and biological activity of ophiobolins have been described.

Effects of gabergic anthelmintics at higher concentrations on the guanidine-induced twitch responses in isolated frog rectus preparations.

Effects of various gabergic anthelmintics on the guanidine-induced twitch responses in isolated frog rectus preparations were examined. All gabergic anthelmintics such as milbemycin oxime, milbemycin D, avermectin B1a, ivermectin, and diethylcarbamazine (DEC) showed stimulatory effects on the guanidine-induced twitch responses at their higher concentrations. Only piperazine caused inhibitory effects on the twitch responses, even at higher concentrations. The stimulation of the twitch responses by the gabergic anthelmintics was antagonized with tetrodotoxin, hemicholinium-3, d-tubocurarine, and strychnine. These results suggest that all gabergic anthelmintics except piperazine stimulate the release of acetylcholine from the nerve endings and that all of them, including piperazine, have different effects on the gabergic mechanism at lower concentrations and on the cholinergic mechanism at higher concentrations.

In vitro effects of milbemycin oxime: mechanism of action against Angiostrongylus cantonensis and Dirofilaria immitis.

The neuropharmacological mechanisms underlying the action of milbemycin oxime on the motility of Angiostrongylus cantonensis and Dirofilaria immitis were examined in vitro. In A. cantonensis, milbemycin oxime caused inhibitory effects at low concentrations of > or = 10(-9) g/ml, and paralysis was elicited at 10(-8) - 10(-6) g/ml. The paralysis was antagonized by picrotoxin and bicuculline but not by dibenamine. In addition, stimulatory effects were observed when the antibiotic was used at higher concentrations of 3-5 x 10(-6) g/ml, and the action was antagonized by strychnine. Both effects were also observed in the preparation contracted by eserine or pyrantel. When D. immitis was treated with milbemycin oxime at concentrations of 10(-7) and 3-5 x 10(-6) g/ml, only slight inhibitory and stimulatory effects, respectively, were observed. These effects were partially antagonized by picrotoxin and strychnine, respectively. These results suggest that the inhibitory and stimulatory actions of milbemycin oxime are caused through gabergic and cholinergic mechanisms in A. cantonensis and D. immitis.

Triphasic locomotor response of a plant-parasitic nematode to avermectin: inhibition by the GABA antagonists bicuculline and picrotoxin.

The response of the plant parasitic nematode, Meloidogyne incognita (J2 stage) to avermectin B2a-23-one is triphasic, comprising an initial loss of locomotor activity where the juveniles remain sensitive to touch, a recovery phase and a final loss of activity where the juveniles are relatively insensitive to touch. In contrast, the acetylcholinesterase inhibitor, oxamyl, causes initial hyperactivity of juveniles followed by a progressive decline in movement. The addition of bicuculline and to a lesser extent picrotoxin, both antagonists of gamma-aminobutyric acid (GABA), blocks the action of avermectin on M. incognita.

Some pharmacological effects of the nematocide, morantel.

1. In isolated nerve-muscle preparations as well as in nerve-muscle preparations in intact anaesthetized animals, morantel exhibited neuromuscular blocking properties similar to those of depolarizing blockers. The drug also caused spastic paralysis of 3 day-old chicks and contracture of the isolated toad rectus abdominis muscle.2. Morantel caused contraction of the guinea-pig and rabbit isolated small intestine. This effect was antagonized by atropine and hexamethonium.3. Morantel caused an increase in the blood pressure of the anaesthetized rat and cat and contraction of the nictitating membrane of the anaesthetized cat. These effects were antagonized by hexamethonium.4. It was concluded that morantel (like the related compound pyrantel) has acetylcholine-like action and that its structure is consistent with such action.

Aspects of the pharmacology of a new anthelmintic: pyrantel.

1. The pharmacological properties of an anthelmintic, pyrantel, and some of its analogues have been described and compared with piperazine in a variety of vertebrate and helminth preparations.2. Pyrantel and its analogues in common with nicotine and decamethonium cause spastic paralysis in chicks and contracture of the chick semispinalis and toad rectus abdominis muscles.3. In the soleus and anterior tibialis muscles of the cat, pyrantel in large amounts caused a short-lived neuromuscular block that was preceded by initial depolarization.4. In preparations from cat and rat, pyrantel showed properties common to both competitive and depolarizing neuromuscular blocking drugs.5. Pyrantel blocked the contracture evoked by transmural stimulation and caused a marked contracture of the worm. Piperazine caused a gradually developing reduction in the responses to transmural stimulation and no contracture.6. Pyrantel and its analogues caused a slowly developing contracture of strip preparations of Ascaris, being more than 100 times more active than acetylcholine in this respect. Piperazine caused a relaxation of Ascaris strip preparations and in common with (+)-tubocurarine blocked the responses to acetylcholine and pyrantel analogues on this preparation.7. Pyrantel caused depolarization and increased spike discharge frequency in single muscle cells of Ascaris, these changes being accompanied by increase in tension. Piperazine, on the other hand, caused hyperpolarization and reduction in spike discharge frequency and relaxation, and antagonized the effects of pyrantel.