Chloride channel activators

The mechanism by which the methylxanthines produce CNS stimulation is not clearly estabUshed. These agents may function, ia part, to limit chloride channel activation ia a manner similar to that of pentylenetetra2ol (7) or hicuculline (8). Another possibiUty is a specific antagonism of the inhibitory neurotransmitter adenosiae [58-61-7] (19) (19). 

Some quinolizinium derivatives such as MPB-07 60 have importance as chloride channel activators. This compound has been shown to be photolabile in aqueous solution when exposed to daylight, being transformed into the phenolic derivative 62 with the deprotonated form 61 as an intermediate, as shown in Scheme 1 <2002JPS324>. A highly regioselective solid-state photodimerization of naphthoquinolizinium salts has also been described <2002EJO2624>. 

Lubiprostone is a chloride channel activator that acts locally on the gut to accelerate genitourinary transit time and delay gastric emptying. It is approved for chronic idiopathic constipation in adults. The dose is 24 mg capsule twice daily with food. Lubiprostone may cause headache, diarrhea, and nausea. 

Zerangue, N. and Kavanaugh, M. P. (1996) ASCT-1 is a neutral amino acid exchanger with chloride channel activity. J. Biol. Chem. 271, 27991-27994. 

Fig. 2. Schematic diagram of the stoichometry of ion flux coupling and the chloride channel activity of glutamate transporters. Glutamate is coupled to the co-transport of 3 Na+, 1K+, and the countertransport of 1 K+. In addition, glutamate and Na+ binding to the transporter activates an uncoupled chloride flux through the transporter.

The field of gastrointestinal drugs saw the entry of Amitiza (lubiprostone), the first selective and locally acting CIC-2 chloride channel activator, for the... 

Another suggested mechanism of action involves the chloride channel. As discussed previously, the chloride channel is intimately associated with neuronal inhibition, and its activity appears to be modulated at many different sites. Caffeine can compete for binding at the benzodiazepine site and would therefore be expected to reduce chloride conductance. Thus, caffeine may act functionally like the analeptic stimulants that limit chloride channel activation. 

Chloride channel activator Lubiprostone, prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content... 

Chloride channel activator Lubiprostone (see above) useful in constipation-predominant IBS in women ... 

Johanson JF et al Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-active type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008 103 170. [PMID 17916109]... 

Tominaga M, Tominaga T, Miwa A, et al. Volume-sensitive chloride channel activity does not depend on endogenous P-glycoprotein. J Biol Chem 1995 270 (46) 27887-27893. 

GABA-gated chloride channels Cyclodienes, lindane, phenylpyrazoles, Avermectins, emamectin benzoate, milbemectin Antagonism Chloride channel activators... 

Indications Constipation, Irritable bowel syndrome Category Chloride channel activator Half-life 0-1.4 hours... 

As shown in Fig. 5.11, the GABA receptor complex also has binding sites for drugs such as barbiturates and benzodiazepinesas well as for certain convulsive agents such as picro-toxin which inhibit chloride channel activity. GABA receptors, their diversity, and pharmacology have been extensively reviewed (123-128). 

T. Pittema, Chloride Channel Activators/New Natural Products (Avermectins and Milbemycins) m Modern Crop Protection Compounds, eds., W. Kramer and U. Schirmer, Wiley-VCH, Weinheim, 2007, Vol. 3, Chapter 29.6, pp. 1069-1088. 

Chloride Channel Activators/Neiv Natural Products (Avermectins and MUbemycins) 11069... 

Chloride Channel Activators/New Natural Products (Avermectins and Milbemycins)... 

To date, three compounds from this group of chloride channel activators (aba-mectin, emamectin benzoate, and milbemectin) have been commercialized in crop protection. In addition, a development compound has become known as lepimectin (provisionally approved ISO common name). In this introduction, the origin, synonyms and physicochemical properties of the marketed compounds [1] are summarized (see Tables 29.6.1 and 29.6.2). Further aspects will be discussed in detail in the following sections, such as their mode of action, discovery, chemistry, insecticidal activity, agronomic use, and safety. Several recent reviews cover... 

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