氨基甲酸酯類殺蟲劑藥理學(xué)

1、1 Chapter 3: Carbamate Insecticides l1. Development lThe carbamate insecticides are the latest arrival in the field of anticholinesterase insecticides, and at present many new compounds are still in the process of being marketed. 2 Carbamate Insecticides lIn general, carbamate insecticides are synth

2、etic derivatives of physostigmine (commonly called eserine), which is the principal alkaloid of the plant Physostigma venenosum (calabar beans). 3 Carbamate Insecticides lPhysostigma venenosum (calabar beans). 4 Carbamate Insecticides lThe Chemical structure of eserine was analysed in 1925 5 Carbama

3、te Insecticides lPhysostigmine was known to be an inhibitor of cholinesterase, and Stedman and Eason (1932) worked to develop synthetic analogues, such as prostigmine. 6 Carbamate Insecticides lAlthough these and similar compounds are effective inhibitors of insect cholinesterase, they are unsuitabl

4、e as insecticides, for they are water-soluble quaternary salts or amine hydrochlorides and hence too polar to penetrate the insect cuticle. 7 Carbamate Insecticides lKolbezen attributed their ineffectiveness as insecticides to their low lipoid solubility. OBrien considered that the ion-impermeable s

5、heath of the insect nerve would also contribute to their ineffectiveness, for these drugs were ionized at physiological pH and would therefore be excluded from their site of action. 8 Carbamate Insecticides lHence the modern carbamate insecticides have been modified by eliminating the polar moiety o

6、f physostigmine so that they can easily penetrate the insect cuticle as well as the nerve sheath. 9 Carbamate Insecticides lThe general carbamate structure is l O l | l R1NH - C - OR2 l where R1 and R2 are alkyl or aryl groups. 10 Carbamate Insecticides l1. Carbofuran(克百威 ,呋喃丹) is highly toxic,with

7、an acute oral LD50 in rats of 5 mg/Kg. It is effective against soil insects in corn, cotton insects, and pests on potatoes. 11 l2. Temik (aldicarb) is a new type of systemic carbamate insecticide, acaricide, and nematocide which is absorbed into the root system of plants and has a residual life of u

8、p to 10 weeks. Temik is highly toxic, with an acute oral LD50 in rats of 1-30 mg/kg. It is relatively soluble in water. Carbamate Insecticides 12 Carbamate Insecticides l3. Methomyl is a white crystalline solid. It is fairly soluble in water. Its acute oral toxicity to rats is 17 mg/kg. It has, howe

9、ver, a low dermal toxicity (5000mg/kg, rabbits). It is a broad- spectrum insecticide on various vegetables, forage(草料), and some ornamentals. 13 Carbamate Insecticides l4. Propoxur is a contact insecticide which shows systemic action with soil application. It has a rapid knockdown and has a long res

10、idual life. lIt is effectively used against cockroaches, flies, mosquitoes, chinch bugs, and spiders. 14 Action mechanism lInhibition of AChE l1. coulombic binding l2. carbamylation (phosphorylation) l3.decarbamylation (dephosphorylation) +CXE K1K2K3 X CECE+CX.E 15 Action mechanism lCarbamates are p

11、owerful anticholinesterase agents, and act in mammals as parasympathomimetic (擬副交感(神經(jīng))的,類副交感(神經(jīng))的) drugs. 16 Action mechanism lClinically they are used as : l(1) drugs for topical administration as miotic (縮瞳劑) in glaucoma (青光眼). l(2)stimulants of intestinal peristalsis (蠕動). l(3) drugs for treatmen

12、t of urinary retention and for myasthenia gravis (肌 肉衰弱) and muscle spasms(肌肉痙攣). 17 Action mechanism lThe basic difference between medical and insecticidal carbamates is that the former compounds always possess either a quaternary or a basic nitrogen group which can attack the anionic site of choli

13、nesterase, whereas the latter compounds are never basic (i.e., ionization reduces the ability of the compounds to penetrate the insect cuticle as well as the nerve sheath) 18 Action mechanism l1. Symptoms lThe symptoms in insects are primarily those of poisoning of the central nervous system. lThe a

14、ction of the carbamate may be blocked by application of nicotine, atropine(阿托品), or barbituric acid （巴比妥酸） to the ganglion（神經(jīng) 節(jié)）. 19 Action mechanism lCarbamates are effective insecticides by virtue of their ability to inhibit AChE in the nervous system. lThe site for carbamylation of the enzyme is

15、the hydroxyl moiety of the serine amino acid. 20 Action mechanism lCarbamates are as potent cholinesterase inhibitors as organophosphates are, and they behave in an almost identical manner in biological systems, with certain differences. 21 Action mechanism lCertain carbamates are very selective inh

16、ibitors of cholinesterase and not of aliesterase. The selectivity of carbamates is sometime more pronounce against the cholinesterases of different species. 22 Action mechanism lThe second important difference between the action mechanism of carbamates and that of organophosphates is that the primar

17、y mode of cholinesterase inhibition by carbamates is apparently reversible. 23 Action mechanism lThere are one factor contributing to this reversibility. The step 3 reaction is easy for carbamates, yielding the original enzyme, which results in the appearance of recovery. 24 Action mechanism lThe de

18、carbamylation process (step 3) can be speeded up by the addition of hydroxylamine to the inhibited cholinesterase, as is the case with phosphorylated cholinesterases, but unlike the latter cases, 2-PAM does not show recovery activity on the carbamylated enzymes. 25 Action mechanism lThe initial step

19、 of complex formation (step 1) is favored by nucleophilic substitution, while step 2 is enhanced by electrophilic substitution. lIn carbamate inhibiton, the important process appears to be step 1. 26 Action mechanism lCarbamates, like organophosphates, can inhibit esterases that have serine in their

20、 catalytic centre; these are called serine- esterases or beta- esterases. 27 Action mechanism lAlthough the inhibition of serine- esterases other than AChE is not significant for the toxicity of the compounds, it may have significance for the potentiation of toxicity of other compounds after long-te

21、rm low-level exposure. 28 Action mechanism lThe spontaneous reactivation of various carbamylated ChEs expressed as half-life, at pH 7.0 - 7.4 and 25 ranged between 2 and 240 min for AChE. 29 Action mechanism lThe rate of regeneration of the carbamylated enzyme to AChE is relatively rapid compared wi

22、th that of an enzyme that has been inhibited (phosphorylated) by an organophosphorus pesticide. 30 Action mechanism lMechanism differences between carbamates and OP insecticide l1. carbamylation, phosphorylation l2. Selectivity of carbamate against cholinesterase of different species. l3.Recovery sp

23、eed l4.No aging for carbamylated AChE. l5.Therapy: Only atropine for carbamylation 31 Action mechanism lCarbamylation lAChE serine: hydroxyl group l react with lCarbamate: carbonyl group lKi : bimolecular rate constant. 32 Action mechanism lI50=0.693/(Ki* t) lI50 is the concentration of inhibitor resulting in loss of 50 per cen