Dihydroavermectin

Since ivermectin (= 22,23-dihydroavermectin B ) is obtained by catalytic reduction of avermectin B, the same procedure using tritium gas convenientiy affords tritiated ivermectin (22,23- [JT]-22,23-dihydroavermectin B ). The preparation of a tritiated derivative containing a 22,23-double bond starts with the readily available 5-ketone, which is reduced with [JT]-sodium borohydride stereospecificaHy to a 5- [JT]-derivative (40). Carbon-14 labeled avermectins can be obtained by a biosynthetic process using sodium (l- C)propionate as labeled precursor (48). 

The microorganism was classified as a new species of actinomycete. Streptomyces avermitilis. Its anthelmintic activity was shown to reside in 8 closely related macrocyclic lactones, named avermectins, which were also found to possess activity against free-living and parasitic arthropods. One of the natural components, avermectin is now being evaluated as a pesticide for the control of mites of citrus and cotton crops and control of the Red Imported Fire Ant. A chemical derivative, 22,23-dihydroavermectin or ivermectin, has been developed as an antiparasitic agent. It is being marketed for use in cattle, horses and sheep and is expected to become available for swine and dogs. 

Avermectins and Ivermectin. The avermectins are pentacydic lactones isolated from fermentation products of Streptomyces avermitilisy and ivermectin is a semisynthetic chemical, 22,23-dihydroavermectin B1 (46). Ivermectin is effective in very low doses for the control of red spider mites on deciduous fruits, in baits for the control of imported fire ants, and as a parasiticide for Onchocerca volvulus in humans and for catde grubs. These insecticides appear to function as agonists for the neuroinhibitory transmitter y-aminobutyric acid (GABA) (see Antiparasitic agents, avermectins). 

Ivermectin is a semisynthetic analog of avermectin B which contains at least 80% of 22,23-dihydroavermectin B,a and not more than 20% of 22,23-dihydroavermectin B,b. It is a potent anthelminthic/insecticide for the control of a wide variety of arthropod parasites, including endoparasites and ectoparasites of animals such as cattle, horses, sheep, swine, and dogs. Its oral LD50 in rats is 650 mg/kg. 

Davies et al. [378b] studied the bioconcentration of ivermectin (22,23-dihy-droavermectin Bj) in mussels Mytilus edulis). Ivermectin has been proposed as a chemotherapeutant for the treatment of farmed salmon infected with sea lice. The commercial ivermectin contains two avermectin derivatives at least 80% of 22,23-dihydroavermectin Bj (C48H74O14 molecular mass 874.5 g mol 0 and not more than 20% of 22,23-dihydroavermectin Bjb (C47H72O14, molecular mass 860.5 g mol 0- Both compounds possess nearly the same molecular dimensions with the same cross-section of ca. 25 A as avermectin Bj. The water solubility of ivermectin is low, between 6 and 9 pg 1. For comparison, the solubility of hexachlorobenzene (HCB) in water is 5 pg h. ... 

Thermospray mass spectra often provide excellent molecular weight information, with some additional structural information being provided by fragment ions, via an ionization mechanism similar in "softness" to chemical ionization ( Cl ) Q) Spectra obtained by previous researchers from 22,23 dihydroavermectin Bia, a macrolide similar in structure to the nemadectins, demonstrated that chemical ionization mass spectrometry (A) and thermospray LC/MS (5.) provided excellent results. We anticipated, therefore, that the nemadectins would also be amenable to thermospray LC/MS analysis. 

These 3-dimensional structures are shown in Figure 4. The top panel shows avermectin Bia and 22, 23 dihydroavermectin Bia, from which we can see some general features of abamectin and ivermectin that are not obvious from the 2-dimensional representation. These include the rigid, corrugated planar form of... 

Figure 4. Molecular models of avermectins used in the specificity studies of Table I. Top panel avermectin Bia (left) and 22,23,dihydroavermectin Bia (right). Middle panel avermectins Bia (left) and B2a (right). Note differences in the C22 — C23 bonding, and its effect on orientation of the R2 ethyl group (arrows) in these free energy-minimized structures. Bottom panel avermectins A2a (left) and B2a (right), oriented to show the OCH3 or OH groups at R3 (arrows).

Mrozik et al. [67] have converted the 22,23-dihydroavermectins and (140b, R=OH) into 13-deoxy-22,23-dihydroavermectin B and B, aglycones (140a, R=H) corresponding to 26-ethylmilbemycin-aj and milbemycin-B41D, respectively. Later the total synthesis of milbemycin-(3j (141) was developed [123,124]. 

Avermectin Bia has been shown to stimulate chloride ion uptake into cockroach muscle ( 140 and block transmission at the arthropod neuromuscular junction by increasing GABA-mediated chloride ion permeability (15), (16). To extend our understanding of ion channel types present in the surface membrane of the synaptosome we examined the effects of ivermectin (22,23-dihydroavermectin B.) and some closely related milbemycins. Both ivermectin and the milbemycins examined, with the exception of milbemycin a9, were... 

We have shown that the anthelmintics pyrantel, morantel and levamisole, activate acetylcholine (Ach) receptors on the muscle cell membranes of Ascaris suum and also that the avermectin 22,23-dihydroavermectin Bla (DHAVM) blocks the function of muscle cell gamma-aminobutyric acid (GABA) receptors. In experiments using micro-iontophoresis, the cholinergic anthelmintics were found to act directly on the muscle bag membrane, evoking a depolarizing response. 

The Effects of 22,23-Dihydroavermectin Bla on the Function of Muscle GABA Receptors... 

Figure 7. Effect of prolonged (25 min) bath application of 22,23-dihydroavermectin Bla (DHAVM, 10 ug/ml) on the amplitude of iontophoretically evoked GABA hyperpolarizations a) Examples of GABA responses recorded before and after DHAVM application b) Plot of GABA response amplitude versus time DHAVM was first dissolved in dimethylsulfoxide (DMSO) and then diluted with saline the final DMSO concentration in saline of 1% had no detectable effect in control experiments ...

Figure 8. Effect of brief (2 min) application of 22,23-dihydroavermectin Bla (DHAVM, 0.01 ug/ml) on the conductance increase evoked by GABA, a) Control response evoked by GABA (10 uM), b) co-application of GABA and DHAVM. Both GABA and DHAVM were applied by microperfusion.

Figure 9. a) Current-voltage relationship for GABA currents recorded in the presence (O) and absence ( ) of 0.1 ug/ml 22,23-dihydroavermectin Bla (DHAVM). The DHAVM was applied for 30 min. Both GABA and DHAVM were applied by microperfusion, b) The percentage inhibition of the peak GABA-induced current is plotted as a function of membrane potential for 3 different cells (l,(D,A) each exposed to 0.1 ug/ml DHAVM. 

Fig. 1. Ivermectin [70288-86-7] is a mixture containing at least 80% 22,23-dihydroavermectin Bla [70161-11-4], wherein R = C2H5, and not more than 20%...

Ivermectin is a macrolide compound derived from abamectin, a metabolite produced by Streptomyces avermitilis. More precisely, it is a mixture of two compounds, 22,23-dihydroavermectin (80%) and 22,23-dihydroavermectin (20%) (12). It is widely... 

Ivermectin. 22,23-Dihydroabamectin 22,23-dihydroavermectin B, 22,23-dihydro C-076B, MK-933 Cardomec Eqvalan Heartgard 30 Ivomec Mectizan Zimecterin. Semi-synthetic deriv of abamectin, q. v.. one of the avermectins, q.v Ivermectin contains at least 80% of... 

---