Open channel blocker

Psychotomimetic Drugs. Figure 2 Chemical structures of the dissociative anesthetics phencyclidine (PCP) and ketamine. Both are arylcycloalkylamine derivatives that are open channel blockers of the NMDA channel. 

Some antagonists combine the ability to block open ion channels with a competitive action at or near the agonist binding site. A well-characterized example is the nicotinic blocker tubocurarine (see Chapter 6). Agonists may also be open channel blockers, thus limiting the maximal response that they can elicit. Such agents (e g., decamethonium) may therefore behave as partial agonists when tested on an intact tissue ... 

C. Here, B is assumed to combine mainly with the active forms of the receptor to form complexes (BR, ABR ) that are inactive. An example is the action of an open channel blocker. Note the convergence of the curves at low agonist concentrations (contrast with the pattern expected for noncompetitive antagonism, as in panel A and as shown in Figure 1.26). 

When an open channel blocker is added, the popm in the presence of the blocker (pblocker) given below is a function of both agonist (A) and blocker (B) concentration ... 

This result is also of importance because it shows that simple open-channel blockers do not reduce the charge passed by the channel during each activation so they will not reduce the charge ... 

Slow-channel syndrome. Abnormally long-lived openings of mutant AChR channels result in prolonged endplate currents and potentials, which in turn elicit one or more repetitive muscle action potentials of lower amplitude that decrement. The morphologic consequences stem from prolonged activation of the AChR channel that causes cationic overload of the postsynaptic region - the endplate myopathy - with Ca2+ accumulation, destruction of the junctional folds, nuclear apoptosis, and vacuolar degeneration of the terminal. Some slow-channel mutations in the transmembrane domain of the AChR render the channel leaky by stabilization of the open state, which is populated even in the absence of ACh. Curiously, some slow-channel mutants can be opened by choline even at the concentrations that are normally present in serum. Quinidine, an open-channel blocker of the AchR, is used for therapy. 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

Tse, H.-F., Zhang, S. and Li, G.-R. (2008) The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-a-go-go-related gene (hERG) potassium channels. British Journal of Pharmacology, 81, 1-9. 

Although the hypothesis underlying the ability of this moderate affinity open channel blocker to differentiate between phasic physiological and tonic excitotoxic pathological activation of NMDA receptors has gained relatively wide acceptance (Mealing et al. 1997 Kornhuber and Weller 1997 Parsons et al. 1999) it is still unclear how such compounds could differentiate between normal and abnormal synaptic activation of NMDA receptors. 

Within the channel pore there is also the binding site for the so-called open channel blockers which is also able to... 

Buisson B. and Bertrand D. (1998). Open-channel blockers at the human a4/32 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53 555-563. 

Lipton S. A. (1993). Prospects for clinically tolerated NMDA antagonists open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci. 16 527-532. 

Zhao X, Yeh JZ, Salgado VL, and Narahashi T (2004) Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons. The Journal of Pharmacology and Experimental Therapeutics 310 192-201. 

Chen HSV, Wang YF, Rayudu PV et al 1998 Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience 86 1121—1132... 

Horn I had the impression that they found a voltage dependence that looked like open channel block voltage dependence. They had a channel that didn t inactivate and they could see it as a charged open channel blocker entering the electric field. It seems to me that there is some inconsistency here I don t see how it is entering the electric field if it is at the very mouth of the channel. 

A number of invertebrate polyamine toxins have recently been shown to be open channel blockers of glutamate receptors initially at the neuromuscular junction of locusts [54] and recently on central mammalian neurones [54-57], These toxins include argiotoxin 636, Joro spider toxin and philanthotoxin. Although these polyamine toxins block NMDA receptors at least in some preparations, in others they also block responses mediated by AMPA receptors more selectively [58-60]. 

Tubocurarine - Open Channel Blocker With Low Unblocking Rate... 

How then do these single channel data on the action of (+)-TC relate to the effect of this compound on the whole nerve-muscle preparation If (+)-TC is perfused over the locust retractor unguis nerve-muscle preparation (15, 53) at concentrations > 10 5M there is a reduction in the amplitude of the neurally-evoked twitch of the retractor unguis muscle. The magnitude of this reduction in twitch amplitude is directly proportional to the frequency of stimulation of the muscle (49) These observations are entirely consistent with the notion the (+)-TC is an open channel blocker with a relatively low unblocking rate. 

Philanthotoxin - Open Channel Blocker with Complex Unblocking Kinetics... 

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