1、1,Chapter 3: Carbamate Insecticides,1. Development The 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,In general, carbamate insecticides are syntheti
2、c derivatives of physostigmine (commonly called eserine), which is the principal alkaloid of the plant Physostigma venenosum (calabar beans).,3,Carbamate Insecticides,Physostigma venenosum (calabar beans).,4,Carbamate Insecticides,The Chemical structure of eserine was analysed in 1925,5,Carbamate In
3、secticides,Physostigmine was known to be an inhibitor of cholinesterase, and Stedman and Eason (1932) worked to develop synthetic analogues, such as prostigmine.,6,Carbamate Insecticides,Although these and similar compounds are effective inhibitors of insect cholinesterase, they are unsuitable as in
4、secticides, for they are water-soluble quaternary salts or amine hydrochlorides and hence too polar to penetrate the insect cuticle.,7,Carbamate Insecticides,Kolbezen attributed their ineffectiveness as insecticides to their low lipoid solubility. OBrien considered that the ion-impermeable sheath of
5、 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,Hence the modern carbamate insecticides have been modified by eliminating the polar moiety of physost
6、igmine so that they can easily penetrate the insect cuticle as well as the nerve sheath.,9,Carbamate Insecticides,The general carbamate structure is O | R1NH - C - OR2where R1 and R2 are alkyl or aryl groups.,10,Carbamate Insecticides,1. Carbofuran(克百威 ,呋喃丹) is highly toxic,with an acute oral LD50 i
7、n rats of 5 mg/Kg. It is effective against soil insects in corn, cotton insects, and pests on potatoes.,11,2. 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 up to 10 weeks. Temik
8、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,3. Methomyl is a white crystalline solid. It is fairly soluble in water. Its acute oral toxicity to rats is 17 mg/kg. It has, however, a low dermal toxi
9、city (5000mg/kg, rabbits). It is a broad-spectrum insecticide on various vegetables, forage(草料), and some ornamentals.,13,Carbamate Insecticides,4. Propoxur is a contact insecticide which shows systemic action with soil application. It has a rapid knockdown and has a long residual life. It is effect
10、ively used against cockroaches, flies, mosquitoes, chinch bugs, and spiders.,14,Action mechanism,Inhibition of AChE 1. coulombic binding 2. carbamylation (phosphorylation) 3.decarbamylation (dephosphorylation),15,Action mechanism,Carbamates are powerful anticholinesterase agents, and act in mammals
11、as parasympathomimetic (拟副交感(神经)的,类副交感(神经)的) drugs.,16,Action mechanism,Clinically they are used as : (1) drugs for topical administration as miotic (缩瞳剂) in glaucoma (青光眼). (2)stimulants of intestinal peristalsis (蠕动). (3) drugs for treatment of urinary retention and for myasthenia gravis (肌肉衰弱) an
12、d muscle spasms(肌肉痉挛).,17,Action mechanism,The 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 cholinesterase, whereas the latter compounds are never basic (i.e
13、., ionization reduces the ability of the compounds to penetrate the insect cuticle as well as the nerve sheath),18,Action mechanism,1. Symptoms The symptoms in insects are primarily those of poisoning of the central nervous system. The action of the carbamate may be blocked by application of nicotin
14、e, atropine(阿托品), or barbituric acid（巴比妥酸） to the ganglion（神经节）.,19,Action mechanism,Carbamates are effective insecticides by virtue of their ability to inhibit AChE in the nervous system. The site for carbamylation of the enzyme is the hydroxyl moiety of the serine amino acid.,20,Action mechanism,C
15、arbamates 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,Certain carbamates are very selective inhibitors of cholinesterase and not of aliesterase. The selectivity of
16、carbamates is sometime more pronounce against the cholinesterases of different species.,22,Action mechanism,The second important difference between the action mechanism of carbamates and that of organophosphates is that the primary mode of cholinesterase inhibition by carbamates is apparently revers
17、ible.,23,Action mechanism,There 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,The decarbamylation process (step 3) can be speeded up by the addition of hydr
18、oxylamine 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,The initial step of complex formation (step 1) is favored by nucleophilic substitution, w
19、hile step 2 is enhanced by electrophilic substitution. In carbamate inhibiton, the important process appears to be step 1.,26,Action mechanism,Carbamates, like organophosphates, can inhibit esterases that have serine in their catalytic centre; these are called serine- esterases or beta-esterases.,27
20、,Action mechanism,Although 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-term low-level exposure.,28,Action mechanism,The spontaneous reactivation of va
21、rious 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,The rate of regeneration of the carbamylated enzyme to AChE is relatively rapid compared with that of an enzyme that has been inhibited (phosphorylated) by an organophosp
22、horus pesticide.,30,Action mechanism,Mechanism differences between carbamates and OP insecticide 1. carbamylation, phosphorylation 2. Selectivity of carbamate against cholinesterase of different species. 3.Recovery speed 4.No aging for carbamylated AChE. 5.Therapy: Only atropine for carbamylation,31
23、,Action mechanism,Carbamylation AChE serine: hydroxyl group react with Carbamate: carbonyl group Ki : bimolecular rate constant.,32,Action mechanism,I50=0.693/(Ki* t) I50 is the concentration of inhibitor resulting in loss of 50 per cent of the enzymatic activity after pre-incubating the enzyme for
24、a fixed time.,33,Poisoning and Therapy,Mutagenicity There is little evidence, if any, to suggest that carbamate compounds are mutagenic. An evaluation of the mutagenic potential of carbaryl, methomyl, propoxur, carbofuran, and pirimicarb(抗蚜威), using a variety of microorganisms as indicator strains,
25、produced negative results.,34,Poisoning and Therapy,Carcinogenic action It has never been reported that any of the carbamate insecticides have carcinogenic action; anxiety has arisen from the fact that many analogues of C2H5OC(O)NH2 show such activity.,35,Poisoning and Therapy,阿托品类抗胆碱药即为其特效解毒剂，轻度中毒时肌注0.5-1mg阿托品即可，必要时可重复1-2次；重度中毒时可2-4mg静注，并尽快阿托品化（方法同前），持续4-8h即可，时间无需太长。无需使用肟类化合物，因会加强氨基甲酸酯的毒性。,
