Picrotoxins

Some naturally occurring analeptics have been known for centuries. Two of the best known and most thoroughly studied are strychnine [57-24-9] (1) and picrotoxin [124-87-8] a 1 1 combination of picrotoxinin [17617-45-7] (2) and picrotin [21416-53-5] (3). These continue to be of interest in the study of mammalian neurotransmission. 

Picrotoxin has been instmmental in estabUshing an inhibitory neurotransmitter role for the amino acid, gamma-aminobutyric acid (GABA), quantitatively the most important inhibitory neurotransmitter in the mammalian CNS. Whereas glycine is predominately localized in the spinal cord, GABA... 

Picrotoxin, a potent antagonist of 7-aminobutyric acid at neural synapses, has been synthesized from (R)-(-) carvone as SM-goal (Sections 3.1 and 6.5). 

Dioscorine is bitter and poisonous it produces paralysis of the centra system, and, in general, behaves like picrotoxin. This action PPears to be correlated with the — 0—C = C- group, since on the... 

PICOPURE , hydrogen peroxide, 108 Picric acid, 108 Picrotoxin, 108 Pidilite hidustries Ltd., 174 Piedmont Chemical Industries Inc., 244 Pilot Chemical Company, 244 PILOT , chloi-pyrifos, 108 Pindone, 108... 

Pikro-. picro-. -tozioinsaure, /. picrotoxininic acid, -toxinsaure, /. picrotoxinic acid, Pikryl, n. picryl,... 

The term analeptics refers to convulsants and respiratory stimulants (i.e. central nervous system stimulants). They comprise a reverse group of agents (for example amphifrnazole and doxapram (respiratory stimulants) and strychnine, biculline and picrotoxin). Analeptics are mainly experimental drugs. Only amphifrnazole and doxapram are occasionally used for the treatment of acute ventilatory failure. 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

Picrotoxin is a mixture of pircotin (non-toxic) and picrotoxinin, which occurs in the seeds of the Asiatic climber Anamirta cocculus (levent berry, cockles). It is a non-competitive antagonist at the y -aminobutyric acidA (GABAa) receptor. 

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

GABAc receptors are defined by their insensitivity to bicuculline and their activation by conformationally restricted analogues of GABA such as CACA and (+)-CAMP (15, 2i -2-(aminomethyl)cyclopropanecarboxylic acid). They are blocked by picrotoxin but can be selectively antagonised by TPMPA (l,2,5,6-tetrahydropyridin4-ylphosphinic acid). Unlike GABAa receptors, they are not affected by benzodiazepines, barbiturates or anaesthetics (Barnard et al. 1998 Bormann 2000 Chebib and Johnston 2000). 

Figure 11.9 GAB Ac receptor pharmacology and structure, (a) Various GAB Ac agonists and antagonists described in the text. Picrotoxinin is the active component of picrotoxin and also acts at GABAa receptors, (b) Presumed subunit structures of GABAc receptors. The receptors can form as homomeric assemblies of p subunits but native receptors may be heteromeric assemblies of p subunits (e.g. pi and p2) or may contain both p and y subunits...

Figure 11.10 Glycine receptor pharmacology and structure, (a) Amino acids that act as agonists at glycine receptors, and strychnine a competitive antagonist, (b) Subunit composition of foetal and adult glycine receptors in the spinal cord. The receptors are shown with a pentameric assembly but the a. and subunits are distinct from those that form GABAa receptors. Picrotoxin is also an effective glycine antagonist and in recombinant systems is selective for homomeric receptors...

Experimentally all GABA antagonists induce convulsions. These include the genuine receptor antagonist bicuculline, which competes with GABA for its recognition site on the GABAa receptor and picrotoxin, which binds to a different site more closely related to the chloride ion channel. 

Four glycine receptor subunits have been identified three a subunits and one p subunit. When expressed in heterologous systems, homomeric a receptors generate functional channels, and strychnine and picrotoxin inhibit the current. A more detailed analysis has revealed that the P subunit, probably in the stoichiometry a3P2, is necessary to generate channel properties similar to... 

Bicuculline is an isoquinoline alkaloid elaborated from members of the family Fumariaceae (Papaverales), especially in Corydalis, Dicentra, and Fumaria species. Bicuculline, like picrotoxin, is a specific GABA receptor-blocking agent that impedes the... 

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